APP

Summary

APP (amyloid beta precursor protein, HGNC:620) is a protein-coding gene on chromosome 21q21.3, encoding Amyloid-beta precursor protein (P05067). Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis.

This gene encodes a cell surface receptor and transmembrane precursor protein that is cleaved by secretases to form a number of peptides. Some of these peptides are secreted and can bind to the acetyltransferase complex APBB1/TIP60 to promote transcriptional activation, while others form the protein basis of the amyloid plaques found in the brains of patients with Alzheimer disease. In addition, two of the peptides are antimicrobial peptides, having been shown to have bacteriocidal and antifungal activities. Mutations in this gene have been implicated in autosomal dominant Alzheimer disease and cerebroarterial amyloidosis (cerebral amyloid angiopathy). Multiple transcript variants encoding several different isoforms have been found for this gene.

Source: NCBI Gene 351 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cerebral amyloid angiopathy, APP-related (Definitive, ClinGen) — +8 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 652 total — 23 pathogenic, 9 likely-pathogenic (top 5% of genes corpus-wide)
• GTEx eGene: eQTL in 24 tissues, sQTL in 18 (q < 0.05)
• Phenotypes (HPO): 55
• Drug target: yes — 13 curated mechanism-of-action drugs; 40 molecules with ChEMBL bioactivity (top 1% of genes corpus-wide)
• Approved drugs (ChEMBL mechanism of action): 3 — Aducanumab, Donanemab, Lecanemab
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity little evidence
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.41 (moderately constrained)
• Transcription factor: yes — 31 downstream targets (CollecTRI)
• MANE Select transcript: NM_000484
• Interaction hub: 6,488 STRING partners (top 1% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:620
Approved symbol	APP
Name	amyloid beta precursor protein
Location	21q21.3
Locus type	gene with protein product
Status	Approved
Aliases	alpha-sAPP
Ensembl gene	ENSG00000142192
Ensembl biotype	protein_coding
OMIM	104760
Entrez	351

Gene structure

Transcript identifiers

Ensembl transcripts: 63 — 50 protein_coding, 8 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay, 2 retained_intron

MANE Select: ENST00000346798

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 8, TSL 2: 6, TSL 3: 2, TSL 5: 1

ENST00000346798, ENST00000348990, ENST00000354192, ENST00000357903, ENST00000358918, ENST00000359726, ENST00000415997, ENST00000439274, ENST00000440126, ENST00000448850, ENST00000462267, ENST00000463070, ENST00000464867, ENST00000466453, ENST00000474136, ENST00000491395, ENST00000548570, ENST00000707132, ENST00000707133, ENST00000707134, ENST00000872524, ENST00000872525, ENST00000872526, ENST00000872527, ENST00000872528, ENST00000872529, ENST00000872530, ENST00000872531, ENST00000872532, ENST00000872533, ENST00000872534, ENST00000872535, ENST00000872536, ENST00000872537, ENST00000872538, ENST00000932837, ENST00000932838, ENST00000965079, ENST00000965080, ENST00000965081, ENST00001003894, ENST00001003895, ENST00001003897, ENST00001046380, ENST00001046382, ENST00001086896, ENST00001086897, ENST00001086898, ENST00001107673, ENST00001107674, ENST00001107675, ENST00001107676, ENST00001107677, ENST00001107678, ENST00001107679, ENST00001107680, ENST00001107681, ENST00001114381, ENST00001114382, ENST00001114383, ENST00001114384, ENST00001114385, ENST00001131782

RefSeq mRNA: 11 — MANE Select: NM_000484 NM_000484, NM_001136016, NM_001136129, NM_001136130, NM_001136131, NM_001204301, NM_001204302, NM_001204303, NM_001385253, NM_201413, NM_201414

CCDS: CCDS13576, CCDS13577, CCDS33523, CCDS46638, CCDS46639, CCDS56211, CCDS56212, CCDS56213

Canonical transcript exons

ENST00000346798 — 18 exons

Exon	Start	End
ENSE00001309322	25997360	25997416
ENSE00003691723	26000015	26000182
ENSE00003845466	26170564	26170770
ENSE00003998279	25955627	25955755
ENSE00003998282	26053236	26053348
ENSE00003998285	26051000	26051193
ENSE00003998286	25891722	25891868
ENSE00003998287	25911741	25911962
ENSE00003998288	25954590	25954689
ENSE00003998290	25975070	25975228
ENSE00003998291	26111979	26112146
ENSE00003998292	25905024	25905077
ENSE00003998293	25975954	25976028
ENSE00003998294	25982344	25982477
ENSE00003998296	25897573	25897673
ENSE00003998297	25880550	25881771
ENSE00003998298	26021840	26022042
ENSE00003998299	26089943	26090072

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.79.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 311.6966 / max 5368.2517, expressed in 1755 samples.

Highest expression (Bgee): prefrontal cortex, renal medulla, Brodmann (1909) area 9, medial globus pallidus, stromal cell of endometrium.

Genetic regulation across tissues (GTEx eQTL / sQTL)

APP is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 24 tissues and its splicing (sQTL) in 18 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 42 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Esophagus Muscularis	eqtl	1.4e-17	+0.24	21:26154029:C:A
Cells Cultured fibroblasts	sqtl	7.3e-15	+0.33	21:25999019:A:C
Whole Blood	eqtl	4.9e-13	+0.19	21:26162498:G:A
Nerve Tibial	sqtl	3.4e-12	+0.40	21:25996907:G:A
Adipose Visceral Omentum	sqtl	5.4e-08	+0.41	21:25996907:G:A
Esophagus Gastroesophageal Junction	sqtl	8.2e-08	+0.52	21:25990433:T:C
Esophagus Muscularis	sqtl	9.7e-08	+0.35	21:25991674:A:G
Skin Not Sun Exposed Suprapubic	sqtl	1.2e-07	+0.40	21:25996383:G:A
Artery Tibial	sqtl	1.4e-07	+0.31	21:25996383:G:A
Artery Aorta	sqtl	1.9e-07	+0.43	21:25999019:A:C
Adipose Subcutaneous	sqtl	3.4e-07	+0.32	21:25996907:G:A
Skin Sun Exposed Lower leg	sqtl	4.1e-06	+0.36	21:25995506:C:G
Esophagus Gastroesophageal Junction	eqtl	1.7e-05	+0.23	21:26153541:G:C
Lung	sqtl	1.8e-05	+0.39	21:25999019:A:C
Testis	eqtl	2.6e-05	-0.19	21:26116134:A:G
Adipose Subcutaneous	eqtl	4.9e-05	-0.19	21:25933408:T:G
Thyroid	sqtl	1.1e-04	+0.26	21:25984667:A:T
Heart Left Ventricle	sqtl	1.3e-04	+0.48	21:25997094:T:C
Brain Putamen basal ganglia	eqtl	1.5e-04	+0.14	21:25983644:A:G
Heart Atrial Appendage	sqtl	2.8e-04	+0.45	21:25996383:G:A

FANTOM5 promoters

showing 10 of 17 alternative TSS:

Promoter ID	TPM avg	Samples expressed
189996	294.2522	1754
189952	4.3332	1257
189990	3.2205	1229
189986	2.0240	841
189980	1.6386	649
189987	1.5998	821
189960	1.1338	583
189971	0.9956	564
189994	0.7367	398
189995	0.6492	380

Top tissues by expression

showing 100 of 295 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
prefrontal cortex	UBERON:0000451	99.79	gold quality
renal medulla	UBERON:0000362	99.69	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.69	gold quality
medial globus pallidus	UBERON:0002477	99.66	gold quality
stromal cell of endometrium	CL:0002255	99.65	gold quality
tendon of biceps brachii	UBERON:0008188	99.64	gold quality
cortical plate	UBERON:0005343	99.61	gold quality
globus pallidus	UBERON:0001875	99.58	gold quality
primary visual cortex	UBERON:0002436	99.58	gold quality
islet of Langerhans	UBERON:0000006	99.56	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.56	gold quality
choroid plexus epithelium	UBERON:0003911	99.55	gold quality
metanephros cortex	UBERON:0010533	99.55	gold quality
occipital lobe	UBERON:0002021	99.53	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.51	gold quality
nucleus accumbens	UBERON:0001882	99.47	gold quality
colonic epithelium	UBERON:0000397	99.46	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.46	gold quality
frontal cortex	UBERON:0001870	99.45	gold quality
putamen	UBERON:0001874	99.45	gold quality
gall bladder	UBERON:0002110	99.45	gold quality
ventral tegmental area	UBERON:0002691	99.45	gold quality
caudate nucleus	UBERON:0001873	99.44	gold quality
spinal cord	UBERON:0002240	99.44	gold quality
hypothalamus	UBERON:0001898	99.43	gold quality
endothelial cell	CL:0000115	99.42	gold quality
neocortex	UBERON:0001950	99.41	gold quality
corpus callosum	UBERON:0002336	99.41	gold quality
inferior vagus X ganglion	UBERON:0005363	99.41	gold quality
left lobe of thyroid gland	UBERON:0001120	99.40	gold quality
amygdala	UBERON:0001876	99.40	gold quality
thyroid gland	UBERON:0002046	99.38	gold quality
right lobe of thyroid gland	UBERON:0001119	99.37	gold quality
left adrenal gland	UBERON:0001234	99.35	gold quality
telencephalon	UBERON:0001893	99.35	gold quality
descending thoracic aorta	UBERON:0002345	99.35	gold quality
cerebral cortex	UBERON:0000956	99.34	gold quality
trigeminal ganglion	UBERON:0001675	99.34	gold quality
mucosa of paranasal sinus	UBERON:0005030	99.34	gold quality
left adrenal gland cortex	UBERON:0035825	99.34	gold quality
midbrain	UBERON:0001891	99.33	gold quality
substantia nigra	UBERON:0002038	99.33	gold quality
adrenal gland	UBERON:0002369	99.33	gold quality
adrenal cortex	UBERON:0001235	99.32	gold quality
right frontal lobe	UBERON:0002810	99.32	gold quality
Ammon’s horn	UBERON:0001954	99.31	gold quality
dorsal plus ventral thalamus	UBERON:0001897	99.30	gold quality
right lung	UBERON:0002167	99.30	gold quality
superior vestibular nucleus	UBERON:0007227	99.30	gold quality
right adrenal gland cortex	UBERON:0035827	99.30	gold quality
subthalamic nucleus	UBERON:0001906	99.29	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.29	gold quality
forebrain	UBERON:0001890	99.28	gold quality
substantia nigra pars compacta	UBERON:0001965	99.28	gold quality
pons	UBERON:0000988	99.27	gold quality
right adrenal gland	UBERON:0001233	99.27	gold quality
cingulate cortex	UBERON:0003027	99.27	gold quality
medulla oblongata	UBERON:0001896	99.26	gold quality
central nervous system	UBERON:0001017	99.25	gold quality
rectum	UBERON:0001052	99.25	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.25	gold quality
lateral globus pallidus	UBERON:0002476	99.25	gold quality
anterior cingulate cortex	UBERON:0009835	99.25	gold quality
brain	UBERON:0000955	99.24	gold quality
thoracic aorta	UBERON:0001515	99.21	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	99.21	gold quality
ganglionic eminence	UBERON:0004023	99.21	gold quality
ascending aorta	UBERON:0001496	99.20	gold quality
Brodmann (1909) area 10	UBERON:0013541	99.20	gold quality
dorsal root ganglion	UBERON:0000044	99.19	gold quality
adrenal tissue	UBERON:0018303	99.19	gold quality
smooth muscle tissue	UBERON:0001135	99.16	gold quality
epithelium of mammary gland	UBERON:0003244	99.16	gold quality
temporal lobe	UBERON:0001871	99.14	gold quality
mammary duct	UBERON:0001765	99.13	gold quality
ventricular zone	UBERON:0003053	99.13	gold quality
type B pancreatic cell	CL:0000169	99.12	gold quality
pigmented layer of retina	UBERON:0001782	99.12	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.10	gold quality
tendon	UBERON:0000043	99.09	gold quality
cerebellar cortex	UBERON:0002129	99.09	gold quality
cerebellar hemisphere	UBERON:0002245	99.09	gold quality
lower esophagus	UBERON:0013473	99.08	gold quality
adult mammalian kidney	UBERON:0000082	99.07	gold quality
aorta	UBERON:0000947	99.06	gold quality
transverse colon	UBERON:0001157	99.05	gold quality
kidney	UBERON:0002113	99.05	gold quality
upper lobe of left lung	UBERON:0008952	99.03	gold quality
metanephros	UBERON:0000081	99.01	gold quality
cortex of kidney	UBERON:0001225	99.01	gold quality
superior frontal gyrus	UBERON:0002661	99.00	gold quality
sural nerve	UBERON:0015488	99.00	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.00	gold quality
upper lobe of lung	UBERON:0008948	98.99	gold quality
epithelial cell of pancreas	CL:0000083	98.96	gold quality
popliteal artery	UBERON:0002250	98.94	gold quality
calcaneal tendon	UBERON:0003701	98.94	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.94	gold quality
tibial artery	UBERON:0007610	98.94	gold quality
right ovary	UBERON:0002118	98.93	gold quality

Single-cell (SCXA)

Detected in 38 experiment(s), a significant marker in 34.

Experiment	Marker?	Max mean expression
E-CURD-88	yes	2964.07
E-CURD-112	yes	1694.18
E-HCAD-56	yes	1361.47
E-MTAB-9435	yes	781.93
E-GEOD-150728	yes	658.52
E-GEOD-149689	yes	619.29
E-MTAB-6819	yes	321.97
E-MTAB-8142	yes	121.08
E-MTAB-6701	yes	119.49
E-HCAD-4	yes	71.80
E-MTAB-10287	yes	70.18
E-MTAB-10553	yes	64.61
E-HCAD-1	yes	46.89
E-GEOD-135922	yes	43.26
E-HCAD-6	yes	34.40

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Caudate putamen	tissue	1066.9
Frontal cortex	tissue	972.7
Postcentral gyrus	tissue	850.9
Midbrain	tissue	756.2
Cerebral cortex	tissue	753.0	medium
Somatosensory cortex	tissue	753.0
Nucleus accumbens	tissue	742.4
Thalamus	tissue	726.1
Pons	tissue	701.5
Superior colliculi	tissue	694.8
Choroid plexus	tissue	691.5
Occipital cortex	tissue	669.7
Motor cortex	tissue	662.5
Prefrontal cortex	tissue	661.1
Locus coeruleus	tissue	615.9
Hippocampus	tissue	608.6	medium
Retrosplenial and cingulate cortex	tissue	593.4
Substantia nigra	tissue	572.4
Spinal cord	tissue	571.6
Hippocampal formation	tissue	565.4
Entorhinal cortex	tissue	565.4
Putamen	tissue	559.6
Medulla oblongata	tissue	556.0
Retrosplenial cortex	tissue	542.8
Corpus callosum	tissue	529.3
Ventral forebrain	tissue	515.7
Temporal cortex	tissue	512.3
Basal ganglia	tissue	495.4	medium
Insular cortex	tissue	482.0
Septum	tissue	474.0
Kidney	tissue	464.8	not detected
Thyroid gland	tissue	434.2	not detected
Hypothalamus	tissue	428.5
Adrenal gland	tissue	422.0	not detected
Placenta	tissue	417.2	low
Ovary	tissue	401.1	not detected
Periaqueductal gray	tissue	396.6
Breast	tissue	392.7	low
Amygdala	tissue	375.4
Heart muscle	tissue	356.3	not detected
Smooth muscle	tissue	353.7	not detected
Olfactory bulb	tissue	353.0
Colon	tissue	322.5	low
Gallbladder	tissue	321.7	low
Seminal vesicle	tissue	315.9	low
Pancreas	tissue	305.2	low
Cerebellum	tissue	303.3	high
Rectum	tissue	296.0	low
Fallopian tube	tissue	289.3	not detected
Urinary bladder	tissue	275.5	not detected
Parathyroid gland	tissue	259.7	not detected
Lung	tissue	255.6	not detected
Endometrium 1	tissue	254.0	not detected
Liver	tissue	251.5	not detected
Cervix	tissue	239.9	not detected
Prostate	tissue	232.5	low
Adipose tissue	tissue	220.7	not detected
Epididymis	tissue	214.2	low
Duodenum	tissue	204.9	low
Stomach 1	tissue	197.5	not detected

Brain sub-regions (HPA Brain Atlas): detected in 190; highest nTPM — Occipital cortex (white matter) (921.2), Corpus callosum, splenium (white matter) (884.6), Parieto-temporal junction (white matter) (880.1), Median raphe nucleus (879.4), Corpus callosum, genu (white matter) (855.7).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

showing 30 of 31 targets:

Target	Regulation
ABCB1	Repression
ABCC1	Unknown
AGER	Activation
ARG1	Activation
AXIN2	Repression
BECN1	Repression
CCL2	Repression
CCL5	Activation
CCND1	Activation
CLU	Repression
DKK1	Activation
EGR1	Activation
FCGR2B	Activation
FOS	Activation
FZD5	Unknown
IL10	Activation
IL1B	Activation
KLF10	Activation
LEF1	Repression
LRP1	Repression
MME	Unknown
NAB2	Activation
NEDD4	Activation
PFKFB3	Activation
PTEN	Activation
ROCK1	Activation
SLC40A1	Repression
SLC8A2	Unknown
SLC8A3	Unknown
TNF	Repression

Upstream regulators (CollecTRI, top): AHR, AP1, AR, BSX, CEBPG, CNOT4, CTCF, CTNNB1, EGR1, ESR1, ESR2, ETS2, FOS, FOXI1, FOXO3, HDAC9, HIF1A, JUN, KAT7, LEF1, MBD2, MYC, NCOR2, NFATC2, NFIL3, NFKB, NR1I2, NR1I3, PPARA, PPARG, PURA, RARA, RXRA, SMAD2, SMAD3, SMAD4, SP1, SP3, STAT1, STAT3

miRNA regulators (miRDB)

Targeting APP by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 137 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-627-3P	99.90	71.42	3316

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.41, missense Z 2.26 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000346798 — one region, missense o/e 0.84. ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 1 (little evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Kunitz protease inhibitor (KPI) domain forms of APP regulate extracellular cleavage of secreted APP by inhibiting the activity of a secreted APP-degrading protease (PMID:10561592)
• Alzheimer’s Amyloid-beta peptide contains catalase binding site and inhibits anti-oxidant activity (PMID:10567208)
• Mutations in APP may predispose to very-late-onset Alzheimer disease. (PMID:11500807)
• helix-containing intermediates in amyloid beta-protein fibrillogenesis (PMID:11580253)
• Serine phosphorylation site within the Alzheimer’s Amyloid-beta sequence (PMID:11726805)
• Here the technique of small angle neutron scattering has been used to determine the structure of these Abeta micelles (PMID:11756677)
• Insulin-degrading enzyme rapidly removes the beta-amyloid precursor protein intracellular domain (AICD). (PMID:11809755)
• Estrogen lowers Alzheimer beta-amyloid generation by stimulating trans-Golgi network vesicle biogenesis (PMID:11823458)
• a biomarker for Alzheimer disease (PMID:11831556)
• Tyrosine phosphorylation of the beta-amyloid precursor protein cytoplasmic tail promotes interaction with Shc. (PMID:11877420)
• mitochondrial dysfunction in Down’s syndrome may lead to intracellular deposition of Abeta42, reduced levels of AbetaPPs, and a chronic state of increased neuronal vulnerability. (PMID:11879646)
• early signaling mechanisms involved in Abeta toxicity using the SH-SY5Y neuroblastoma cell line (amyloid beta protein) (PMID:11882652)
• Apolipoprotein E4 potentiates amyloid beta peptide-induced lysosomal leakage and apoptosis in neuronal cells (PMID:11912196)
• Oxidation of methionine 35 attenuates formation of amyloid beta -peptide 1-40 oligomers (PMID:11912198)
• Accelerated plaque accumulation, associative learning deficits, and up-regulation of alpha 7 nicotinic receptor protein in transgenic mice co-expressing mutant human presenilin 1 and amyloid precursor proteins (PMID:11912199)
• binds to G(M1)ganglioside and promotes the soluble amyloid beta protein polymerization (PMID:11915325)
• forms a seed of amyloid beta protein aggregation via binding to G(M1)ganglioside (PMID:11915326)
• natural oligomers of human Abeta are secreted and cerebral microinjection of cell medium containing these oligomers and abundant Abeta monomers but no amyloid fibrils markedly inhibited hippocampal long-term potentiation in rats (amyloid beta protein). (PMID:11932745)
• Activation of Cyclin-Dependent-Kinase-1 by Alzheimer’s Amyloid-beta peptide (PMID:11958860)
• Munc18a acts through direct and indirect interactions with X11 proteins and powerfully regulates APP metabolism and Abeta secretion. (PMID:12016213)
• A second locus for very-late-onset Alzheimer disease: a genome scan reveals linkage to 20p and epistasis between 20p and the amyloid precursor protein region. (PMID:12016588)
• results show that the constrained decapeptide dimers rapidly form an intramolecular, antiparallel beta-sheet and polymerize into amyloid fibrils at low concentrations (PMID:12023906)
• gamma secretase cleavage of APP may contribute to Alzheimer’s disease-related neurodegeneration [GAMMA SECRETASE] (PMID:12032152)
• Rac1 generates reactive oxygen species through beta-amyloid signaling (PMID:12038964)
• mutation of leucine 166 in presenilin-1 affects generation independent of effect on Abea 42 production (PMID:12048239)
• Mechanism of membrane depolarization caused by the Alzheimer Abeta1-42 peptide (PMID:12054502)
• Eliminating membrane depolarization caused by the Alzheimer peptide Abeta(1-42, aggr.). (PMID:12054503)
• REVIEW: the folding pathways of an Alzheimer’s amyloid Abeta-Peptide explored by long time dynamic simulations. (PMID:12069633)
• Mutations that reduce aggregation of the Alzheimer’s Abeta42 peptide: an unbiased search for the sequence determinants of Abeta amyloidogenesis. (PMID:12079364)
• [alpha]-Secretase ADAM10 as well as [alpha]APPs is reduced in platelets and CSF of Alzheimer disease patients. (PMID:12080182)
• Profile of cholesterol-related sterols in aged amyloid precursor protein transgenic mouse brain (PMID:12091492)
• Transcriptional activation and increase in expression of Alzheimer’s beta-amyloid precursor protein gene is mediated by TGF-beta in normal human astrocytes (PMID:12099697)
• Transforming growth factor-beta-induced transcription of the Alzheimer beta-amyloid precursor protein gene involves interaction between the CTCF-complex and Smads (PMID:12099698)
• description of APP binding site for fibrillar Abeta and identification by alanine scanning mutagenesis (PMID:12107175)
• mutations in PSEN1 increase Abeta42 production (PMID:12119298)
• mutant proteins form annular protofibrils (similar to pore-forming bacterial toxins), suggesting that inappropriate membrane permeabilization might be the cause of cell dysfunction and even cell death in amyloid diseases, as Alzheimers and Parkinsons (PMID:12124613)
• Human APP expressed in rat cortical cell neurons in culture is processed to produce amyloid beta and soluible APP. Expression of APP triggers neuronal cell death. (PMID:12128077)
• laminin affects polymerization, depolymerization and neurotoxicity of this protein. (PMID:12128080)
• Several months after intracerebral injections of this protein into betaAPP transgenic mice, cerebral beta-amyloidosis was induced. (PMID:12128081)
• Annexin 5 and apolipoprotein E-2 protect PC12 rat cells against the cytotoxicity of this protein. (PMID:12128082)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	appb	ENSDARG00000055543
danio_rerio	appa	ENSDARG00000104279
mus_musculus	App	ENSMUSG00000022892
rattus_norvegicus	App	ENSRNOG00000006997
drosophila_melanogaster	Appl	FBGN0000108
caenorhabditis_elegans		WBGENE00000149

Paralogs (2): APLP2 (ENSG00000084234), APLP1 (ENSG00000105290)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:88059) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 88 distinct phenotype terms.

Mouse phenotype (MP)	Records
amyloid beta deposits	6
decreased body weight	5
decreased grip strength	5
abnormal astrocyte morphology	4
abnormal locomotor activation	4
astrocytosis	4
abnormal spatial learning	3
abnormal learning/memory/conditioning	3
premature death	3
decreased brain weight	3
increased thigmotaxis	3
decreased locomotor activity	2
decreased exploration in new environment	2
gliosis	2
absent corpus callosum	2
abnormal neuron morphology	2
microgliosis	2
abnormal circadian behavior	2
increased locomotor activity	2
abnormal microglial cell morphology	1
increased circulating calcium level	1
increased neutrophil cell number	1
increased monocyte cell number	1
myoclonus	1
amyloidosis	1

+63 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Radianthus crispa	C0HJU7	100.0%	Diamond
Heteractis magnifica	C0HK72	100.0%	Diamond
Cyriopagopus hainanus	D2Y2G1	100.0%	Diamond
Cyriopagopus schmidti	P0DJ84	100.0%	Diamond
Macaca mulatta	P29216	100.0%	Diamond
Macaca fascicularis	P53601	100.0%	Diamond
Sus scrofa	P79307	100.0%	Diamond
Bos taurus	Q28053	100.0%	Diamond
Canis lupus familiaris	Q28280	100.0%	Diamond
Oryctolagus cuniculus	Q28748	100.0%	Diamond
Ovis aries	Q28757	100.0%	Diamond
Ursus maritimus	Q29149	100.0%	Diamond
Pan troglodytes	Q5IS80	100.0%	Diamond
Cavia porcellus	Q60495	100.0%	Diamond
Saimiri sciureus	Q95241	100.0%	Diamond
Felis catus	P86906	97.5%	Diamond
Stichodactyla helianthus	P31713	92.7%	Diamond
Mesocricetus auratus	Q60559	86.8%	Diamond
Meriones unguiculatus	Q62577	86.8%	Diamond
Equus caballus	P04365	86.6%	Diamond
Dichotomyctere fluviatilis	O73683	83.9%	Diamond
Takifugu rubripes	O93279	80.4%	Diamond
Vespa bicolor	C0LNR2	66.2%	Diamond
Pimpla hypochondriaca	Q8T0W4	66.2%	Diamond
Gallus gallus	P15989	65.3%	Diamond
Pinctada margaritifera	H2A0N9	58.8%	Diamond
Amblyomma hebraeum	Q5VJG2	57.8%	Diamond
Rhipicephalus microplus	P83609	56.6%	Diamond
Austrelaps labialis	B2BS84	54.7%	Diamond
Ixodes scapularis	Q964Q0	53.8%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
GABPA	protein-coding	2551
ATP5PF	protein-coding	522
APP-DT	ncRNA	118568803
CYYR1-AS1	ncRNA	100996571
CYYR1	protein-coding	116159

Protein

Protein identifiers

Amyloid-beta precursor protein — P05067 (reviewed: P05067)

Alternative names: ABPP, APPI, Alzheimer disease amyloid A4 protein homolog, Alzheimer disease amyloid protein, Amyloid precursor protein, Amyloid-beta (A4) precursor protein, Amyloid-beta A4 protein, Cerebral vascular amyloid peptide, PreA4, Protease nexin-II

All UniProt accessions (6): A0A0A0MRG2, A0A140VJC8, E9PG40, P05067, H7C0V9, H7C2L2

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Interaction between APP molecules on neighboring cells promotes synaptogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions. Can promote transcription activation through binding to APBB1-KAT5 and inhibits Notch signaling through interaction with Numb. Couples to apoptosis-inducing pathways such as those mediated by G(o) and JIP. Inhibits G(o) alpha ATPase activity. Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1. By acting as a kinesin I membrane receptor, plays a role in axonal anterograde transport of cargo towards synapses in axons. Involved in copper homeostasis/oxidative stress through copper ion reduction. In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. The splice isoforms that contain the BPTI domain possess protease inhibitor activity. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and leading to mitochondrial dysfunction in cultured cortical neurons. Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1. Amyloid-beta peptides are lipophilic metal chelators with metal-reducing activity. Bind transient metals such as copper, zinc and iron. In vitro, can reduce Cu(2+) and Fe(3+) to Cu(+) and Fe(2+), respectively. Amyloid-beta peptides bind to lipoproteins and apolipoproteins E and J in the CSF and to HDL particles in plasma, inhibiting metal-catalyzed oxidation of lipoproteins. Promotes both tau aggregation and TPK II-mediated phosphorylation. Interaction with overexpressed HADH2 leads to oxidative stress and neurotoxicity. Also binds GPC1 in lipid rafts. More effective reductant than amyloid-beta protein 40. May activate mononuclear phagocytes in the brain and elicit inflammatory responses. Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain. The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis.

Subunit / interactions. Binds, via its C-terminus, to the PID domain of several cytoplasmic proteins, including APBB family members, the APBA family, MAPK8IP1, SHC1 and, NUMB and DAB1. Binding to DAB1 inhibits its serine phosphorylation. Interacts (via NPXY motif) with DAB2 (via PID domain); the interaction is impaired by tyrosine phosphorylation of the NPXY motif. Also interacts with GPCR-like protein BPP, APPBP1, IB1, KNS2 (via its TPR domains), APPBP2 (via BaSS) and DDB1. In vitro, it binds MAPT via the MT-binding domains. Associates with microtubules in the presence of ATP and in a kinesin-dependent manner. Interacts, through a C-terminal domain, with GNAO1. Amyloid-beta protein 42 binds CHRNA7 in hippocampal neurons. Interacts with CPEB1 and AGER. Interacts with ANKS1B. Interacts with ITM2B. Interacts with ITM2C. Interacts with IDE. Homodimerizes; dimerization is enhanced in the presence of Cu(2+) ions and is promoted by heparin binding. Interacts with PLD3. Interacts with VDAC1. Interacts with NSG1; could regulate APP processing. Interacts with SYT7. Interacts (via transmembrane region) with PSEN1; the interaction is direct. Interacts with LRRK2. Interacts (via cytoplasmic domain) with KIF5B. Interacts (via C-terminus) with APBB2/FE65L1 (via C-terminus). Interacts (via intracellular domain) with APBB3. Amyloid-beta associates with HADH2. Soluble APP binds, via its N-terminal head, to FBLN1. Interacts with S100A9. Interacts with FPR2. Interacts with GSAP. Interacts with SORL1 (via N-terminal ectodomain); this interaction retains APP in the trans-Golgi network and reduces processing into soluble APP-alpha and amyloid-beta peptides. Interacts with SORL1. Interacts with SORL1. Interacts with SORL1.

Subcellular location. Cell membrane. Membrane. Perikaryon. Cell projection. Growth cone. Clathrin-coated pit. Early endosome. Cytoplasmic vesicle Endoplasmic reticulum. Golgi apparatus. Early endosome Early endosome Secreted Cell surface Cell surface Nucleus. Cytoplasm.

Tissue specificity. Expressed in the brain and in cerebrospinal fluid (at protein level). Expressed in all fetal tissues examined with highest levels in brain, kidney, heart and spleen. Weak expression in liver. In adult brain, highest expression found in the frontal lobe of the cortex and in the anterior perisylvian cortex-opercular gyri. Moderate expression in the cerebellar cortex, the posterior perisylvian cortex-opercular gyri and the temporal associated cortex. Weak expression found in the striate, extra-striate and motor cortices. Expressed in cerebrospinal fluid, and plasma. Isoform APP695 is the predominant form in neuronal tissue, isoform APP751 and isoform APP770 are widely expressed in non-neuronal cells. Isoform APP751 is the most abundant form in T-lymphocytes. Appican is expressed in astrocytes.

Post-translational modifications. Proteolytically processed under normal cellular conditions. Cleavage either by alpha-secretase, beta-secretase or theta-secretase leads to generation and extracellular release of soluble APP peptides, S-APP-alpha and S-APP-beta, and the retention of corresponding membrane-anchored C-terminal fragments, C80, C83 and C99. Subsequent processing of C80 and C83 by gamma-secretase yields P3 peptides. This is the major secretory pathway and is non-amyloidogenic. Alternatively, presenilin/nicastrin-mediated gamma-secretase processing of C99 releases the amyloid-beta proteins, amyloid-beta protein 40 and amyloid-beta protein 42, major components of amyloid plaques, and the cytotoxic C-terminal fragments, gamma-CTF(50), gamma-CTF(57) and gamma-CTF(59). PSEN1 cleavage is more efficient with C83 than with C99 as substrate (in vitro). Amyloid-beta protein 40 and Amyloid-beta protein 42 are cleaved by ACE. Many other minor amyloid-beta peptides, amyloid-beta 1-X peptides, are found in cerebral spinal fluid (CSF) including the amyloid-beta X-15 peptides, produced from the cleavage by alpha-secretase and all terminating at Gln-686. Proteolytically cleaved by caspases during neuronal apoptosis. Cleavage at Asp-739 by either CASP6, CASP8 or CASP9 results in the production of the neurotoxic C31 peptide and the increased production of amyloid-beta peptides. N-glycosylated. N- and O-glycosylated. O-glycosylation on Ser and Thr residues with core 1 or possibly core 8 glycans. Partial tyrosine glycosylation (Tyr-681) is found on some minor, short amyloid-beta peptides (amyloid-beta 1-15, 1-16, 1-17, 1-18, 1-19 and 1-20) but not found on amyloid-beta protein 38, amyloid-beta protein 40 nor on amyloid-beta protein 42. Modification on a tyrosine is unusual and is more prevelant in AD patients. Glycans had Neu5AcHex(Neu5Ac)HexNAc-O-Tyr, Neu5AcNeu5AcHex(Neu5Ac)HexNAc-O-Tyr and O-AcNeu5AcNeu5AcHex(Neu5Ac)HexNAc-O-Tyr structures, where O-Ac is O-acetylation of Neu5Ac. Neu5AcNeu5Ac is most likely Neu5Ac 2,8Neu5Ac linked. O-glycosylations in the vicinity of the cleavage sites may influence the proteolytic processing. Appicans are L-APP isoforms with O-linked chondroitin sulfate. Phosphorylation in the C-terminal on tyrosine, threonine and serine residues is neuron-specific. Phosphorylation can affect APP processing, neuronal differentiation and interaction with other proteins. Phosphorylated on Thr-743 in neuronal cells by Cdc5 kinase and Mapk10, in dividing cells by Cdc2 kinase in a cell-cycle dependent manner with maximal levels at the G2/M phase and, in vitro, by GSK-3-beta. The Thr-743 phosphorylated form causes a conformational change which reduces binding of Fe65 family members. In dopaminergic (DA) neurons, phosphorylation on Thr-743 by LRKK2 promotes the production and the nuclear translocation of the APP intracellular domain (AICD) which induces DA neuron apoptosis. Phosphorylation on Tyr-757 is required for SHC binding. Phosphorylated in the extracellular domain by casein kinases on both soluble and membrane-bound APP. This phosphorylation is inhibited by heparin. Extracellular binding and reduction of copper, results in a corresponding oxidation of Cys-144 and Cys-158, and the formation of a disulfide bond. In vitro, the APP-Cu(+) complex in the presence of hydrogen peroxide results in an increased production of amyloid-beta-containing peptides. Trophic-factor deprivation triggers the cleavage of surface APP by beta-secretase to release sAPP-beta which is further cleaved to release an N-terminal fragment of APP (N-APP). Amyloid-beta peptides are degraded by IDE. Sulfated on tyrosine residues.

Disease relevance. Alzheimer disease 1 (AD1) [MIM:104300] A form of Alzheimer disease, a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death. It can be associated with cerebral amyloid angiopathy. Alzheimer disease can be associated with cerebral amyloid angiopathy. The disease is caused by variants affecting the gene represented in this entry. Cerebral amyloid angiopathy, APP-related (CAA-APP) [MIM:605714] A hereditary localized amyloidosis due to amyloid-beta A4 peptide(s) deposition in the cerebral vessels. The principal clinical characteristics are recurrent cerebral and cerebellar hemorrhages, recurrent strokes, cerebral ischemia, cerebral infarction, and progressive mental deterioration. Patients develop cerebral hemorrhage because of the severe cerebral amyloid angiopathy. Parenchymal amyloid deposits are rare and largely in the form of pre-amyloid lesions or diffuse plaque-like structures. They are Congo red negative and lack the dense amyloid cores commonly present in Alzheimer disease. Some affected individuals manifest progressive aphasic dementia, leukoencephalopathy, and occipital calcifications. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The transmembrane helix undergoes a conformation change and unravels partially when bound to PSEN1, facilitating cleavage by PSEN1. The basolateral sorting signal (BaSS) is required for sorting of membrane proteins to the basolateral surface of epithelial cells. The GFLD subdomain binds Cu(2+) ions; this promotes homodimerization. The NPXY sequence motif found in many tyrosine-phosphorylated proteins is required for the specific binding of the PID domain. However, additional amino acids either N- or C-terminal to the NPXY motif are often required for complete interaction. The PID domain-containing proteins which bind APP require the YENPTY motif for full interaction. These interactions are independent of phosphorylation on the terminal tyrosine residue. The YENPXY site is also involved in clathrin-mediated endocytosis. The C-terminal region can bind zinc ions; this favors dimerization and formation of higher oligomers. The OX-2 motif shows some similarity to a region in the N-terminus of CD200/MOX2.

Induction. Increased levels during neuronal differentiation.

Miscellaneous. Chelation of metal ions, notably copper, iron and zinc, can induce histidine-bridging between amyloid-beta molecules resulting in amyloid-beta-metal aggregates. The affinity for copper is much higher than for other transient metals and is increased under acidic conditions. Extracellular zinc-binding increases binding of heparin to APP and inhibits collagen-binding. A major isoform. The L-isoforms are referred to as appicans. A major isoform. The L-isoforms are referred to as appicans. The L-isoforms are referred to as appicans. A major isoform.

Similarity. Belongs to the APP family.

Isoforms (11)

UniProt ID	Names	Canonical?
P05067-1	APP770, PreA4 770	yes
P05067-2	APP305
P05067-3	L-APP677
P05067-4	APP695, PreA4 695
P05067-5	L-APP696
P05067-6	APP714
P05067-7	L-APP733
P05067-8	APP751, PreA4 751
P05067-9	L-APP752
P05067-10	APP639
P05067-11	11

RefSeq proteins (11): NP_000475, NP_001129488, NP_001129601, NP_001129602, NP_001129603, NP_001191230, NP_001191231, NP_001191232, NP_001372182, NP_958816, NP_958817 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002223	Kunitz_BPTI	Domain
IPR008154	Amyloid_glyco_extra	Domain
IPR008155	Amyloid_glyco	Family
IPR011178	Amyloid_glyco_Cu-bd	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR013803	Amyloid_glyco_Abeta	Domain
IPR015849	Amyloid_glyco_heparin-bd	Domain
IPR019543	APP_amyloid_C	Domain
IPR019744	APP_CUBD_CS	Conserved_site
IPR019745	Amyloid_glyco_intracell_CS	Conserved_site
IPR020901	Prtase_inh_Kunz-CS	Conserved_site
IPR024329	Amyloid_glyco_E2_domain	Domain
IPR036176	E2_sf	Homologous_superfamily
IPR036454	Amyloid_glyco_heparin-bd_sf	Homologous_superfamily
IPR036669	Amyloid_Cu-bd_sf	Homologous_superfamily
IPR036880	Kunitz_BPTI_sf	Homologous_superfamily
IPR037071	Amyloid_glyco_Abeta_sf	Homologous_superfamily

Pfam: PF00014, PF02177, PF03494, PF10515, PF12924, PF12925

UniProt features (232 total): mutagenesis site 41, strand 29, sequence variant 21, helix 18, binding site 15, site 15, chain 13, splice variant 13, modified residue 11, glycosylation site 10, region of interest 9, disulfide bond 9, turn 7, sequence conflict 5, domain 3, short sequence motif 3, compositionally biased region 3, peptide 2, topological domain 2, signal peptide 1, transmembrane region 1, cross-link 1

Structure

Experimental structures (PDB)

showing 30 of 263 structures by resolution:

PDB	Title	Method	Resolution (Å)
2FMA	Structure of the Alzheimer’s Amyloid Precursor Protein (APP) Copper Binding Domain in …	X-RAY DIFFRACTION	0.85
6NB9	Amyloid-Beta (20-34) with L-isoaspartate 23	ELECTRON CRYSTALLOGRAPHY	1.05
6OIZ	Amyloid-Beta (20-34) wild type	ELECTRON CRYSTALLOGRAPHY	1.1
8T82	Racemic mixture of amyloid beta segment 35-MVGGVV-40 forms heterochiral rippled …	X-RAY DIFFRACTION	1.1
5ONQ	Alzheimer’s Amyloid-Beta Peptide Fragment 29-40 in Complex with Cd-substituted Thermolysin	X-RAY DIFFRACTION	1.17
3JQL	Crystal Structure of the Complex Formed Between Phospholipase A2 and a Hexapeptide …	X-RAY DIFFRACTION	1.2
3PZZ	Structure of an amyloid forming peptide GAIIGL (29-34) from amyloid beta	X-RAY DIFFRACTION	1.29
4PQD	The longer crystal structure of the grow factor like domain from Beta amypoid precusor …	X-RAY DIFFRACTION	1.33
5ONP	Alzheimer’s Amyloid-Beta Peptide Fragment 1-40 in Complex with Cd-substituted Thermolysin	X-RAY DIFFRACTION	1.34
5ONR	Alzheimer’s Amyloid-Beta Peptide Fragment 1-40 in Complex with Thermolysin	X-RAY DIFFRACTION	1.39
4PWQ	HIGH-RESOLUTION CRYSTAL STRUCTURE OF THE E1-DOMAIN of THE AMYLOID PRECURSOR PROTEIN	X-RAY DIFFRACTION	1.4
7OW1	Crystal Structure of TAP01 in complex with amyloid beta peptide	X-RAY DIFFRACTION	1.4
6O4J	Amyloid Beta KLVFFAENVGS 16-26 D23N Iowa mutation	ELECTRON CRYSTALLOGRAPHY	1.4
5VOS	VGSNKGAIIGL from Amyloid Beta determined by MicroED	ELECTRON CRYSTALLOGRAPHY	1.42
3Q2X	Structure of an amyloid forming peptide NKGAII (residues 27-32) from amyloid beta	X-RAY DIFFRACTION	1.45
5TXD	Structure of amyloid-beta derived peptide - NKGAIF	X-RAY DIFFRACTION	1.45
5MYX	Structure of Pyroglutamate-Abeta-specific Fab c#24 in complex with human Abeta-pE3-18	X-RAY DIFFRACTION	1.49
1AAP	X-RAY CRYSTAL STRUCTURE OF THE PROTEASE INHIBITOR DOMAIN OF ALZHEIMER’S AMYLOID …	X-RAY DIFFRACTION	1.5
3IFL	X-ray structure of amyloid beta peptide:antibody (Abeta1-7:12A11) complex	X-RAY DIFFRACTION	1.5
3IFN	X-ray structure of amyloid beta peptide:antibody (Abeta1-40:12A11) complex	X-RAY DIFFRACTION	1.5
4MVK	Crystal structure of an engineered lipocalin (Anticalin US7) in complex with the …	X-RAY DIFFRACTION	1.5
8T89	Racemic mixture of amyloid beta segment 16-KLVFFA-21 forms heterochiral rippled beta-sheet	X-RAY DIFFRACTION	1.5
5AMB	Crystal structure of the Angiotensin-1 converting enzyme N-domain in complex with …	X-RAY DIFFRACTION	1.55
3BKJ	Crystal structure of Fab wo2 bound to the n terminal domain of amyloid beta peptide (1-16)	X-RAY DIFFRACTION	1.59
5MYO	Structure of Pyroglutamate-Abeta-specific Fab c#6 in complex with human Abeta-pE3-12-PEGb	X-RAY DIFFRACTION	1.59
3BAE	Crystal structure of Fab WO2 bound to the N terminal domain of Amyloid beta peptide (1-28)	X-RAY DIFFRACTION	1.59
2FK1	Structure of the Alzheimer’s Amyloid Precursor Protein (APP) Copper Binding Domain in …	X-RAY DIFFRACTION	1.6
3L81	Crystal structure of adaptor protein complex 4 (AP-4) mu4 subunit C-terminal domain, in …	X-RAY DIFFRACTION	1.6
2FJZ	Structure of the Alzheimer’s Amyloid Precursor Protein (APP) copper binding domain …	X-RAY DIFFRACTION	1.61
2FK2	Structure of the Alzheimer’s Amyloid Precursor Protein (APP) Copper Binding Domain in …	X-RAY DIFFRACTION	1.65

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P05067-F1	68.11	0.30

Antibody-complex structures (SAbDab)

33 antibodies co-crystallized with this protein: 2IPU, 2R0W, 3BAE, 3BKJ, 3IFL, 3IFN, 3IFO, 3IFP, 3MOQ, 3U0T, 4HIX, 4M1C, 4OJF, 4ONF, 4ONG, 4XXD, 5CSZ, 5MY4, 5MYO, 5MYX, 5VZY, 5W3P, 6CO3, 7E6P, 7OW1 (+8 more)

Human Protein Atlas

Protein class: Transporters, Transporter channels and pores, Predicted membrane proteins, Predicted secreted proteins, Predicted intracellular proteins, Plasma proteins, Disease related genes, FDA approved drug targets, Small molecule drugs, Human disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): golgi apparatus; vesicles

Antibody reliability (HPA): IH enhanced · IF supported

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (15)

Position	Role
170	required for cu(2+) reduction
197–198	cleavage; by caspases
219–220	cleavage; by caspases
301–302	reactive bond
671–672	cleavage; by beta-secretase
672–673	cleavage; by caspase-6; when associated with variant 670-n-l-671
678–679	cleavage; by ace
687–688	cleavage; by alpha-secretase
690–691	cleavage; by theta-secretase
704	implicated in free radical propagation
706	susceptible to oxidation
711–712	cleavage; by gamma-secretase; site 1
713–714	cleavage; by gamma-secretase; site 2
720–721	cleavage; by gamma-secretase; site 3
739–740	cleavage; by caspase-6, caspase-8 or caspase-9

Ligand- & substrate-binding residues (15)

Position	Role
96–110	heparin
147	Cu(2+)
151	Cu(2+)
168	Cu(2+)
183	Zn(2+)
186	Zn(2+)
187	Zn(2+)
677	Cu(2+)
677	Zn(2+)
681	Cu(2+)
681	Zn(2+)
684	Cu(2+)
684	Zn(2+)
685	Cu(2+)
685	Zn(2+)

Post-translational modifications (12)

Type	Positions
Phosphoserine	198, 206, 441, 730
Sulfotyrosine	217, 262, 336
Phosphotyrosine	497, 757
Phosphothreonine	729, 743
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in ubiquitin)	763

Disulfide bonds (9)

Type	Positions
Disulfide bond	38–62, 73–117, 98–105, 133–187, 144–174, 158–186, 291–341, 300–324, 316–337

Glycosylation sites (10)

Type	Positions
N-linked (glcnac…) asparagine	542, 571
O-linked (galnac…) threonine	633, 651, 652, 663
O-linked (xyl…) (chondroitin sulfate) serine	656
O-linked (hexnac…) threonine	659
O-linked (galnac…) serine	667
O-linked (hexnac…) tyrosine	681

Mutagenesis-validated functional residues (41)

Position	Phenotype
99–102	reduced heparin-binding.
108	loss of the copper binding site in the gfld subdomain; when associated with a-110.
110	loss of the copper binding site in the gfld subdomain; when associated with a-108.
137	binds copper. forms dimer.
141	binds copper. forms dimer.
144	binds copper. no dimer formation. no copper reducing activity.
147–149	50% decrease in copper reducing activity.
147	loss of a copper binding site; when associated with a-151.
147	some decrease in copper reducing activity.
147	binds copper. forms dimer.
147	greatly reduced copper-mediated low-density lipoprotein oxidation.
151	loss of a copper binding site; when associated with a-147.
151	greatly reduced copper-mediated low-density lipoprotein oxidation.
151	binds copper. forms dimer.
198	greatly reduced casein kinase phosphorylation.
206	reduced casein kinase phosphorylation.
499	reduced affinity for heparin; when associated with a-503.
503	reduced affinity for heparin; when associated with a-499.
656	abolishes chondroitin sulfate binding in l-app733 isoform.
676	60-70% zinc-induced amyloid-beta protein 28 aggregation.
681	60-70% zinc-induced amyloid-beta protein 28 aggregation.
684	only 23% zinc-induced amyloid-beta protein 28 aggregation.
695	causes formation of an artifactual disulfide bond with psen1.
704	reduced protein oxidation. no hippocampal neuron toxicity.
706	reduced lipid peroxidation inhibition.

Function

Pathways and Gene Ontology

Reactome pathways

18 curated (TAS) of 69; 12 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

showing 60 of 69 pathways:

ID	Pathway	Evidence
R-HSA-9936900	Aggregated β-amyloid induces FXII autocatalysis ⚕	curated
R-HSA-9936686	Aggregated β-amyloid interacts with fibrinogen ⚕	curated
R-HSA-8862803	Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models ⚕	curated
R-HSA-9660826	Purinergic signaling in leishmaniasis infection ⚕	curated
R-HSA-977225	Amyloid fiber formation	curated
R-HSA-3000178	ECM proteoglycans	curated
R-HSA-444473	Formyl peptide receptors bind formyl peptides and many other ligands	curated
R-HSA-418594	G alpha (i) signalling events	curated
R-HSA-416476	G alpha (q) signalling events	curated
R-HSA-432720	Lysosome Vesicle Biogenesis	curated
R-HSA-9837999	Mitochondrial protein degradation	curated
R-HSA-114608	Platelet degranulation	curated
R-HSA-8957275	Post-translational protein phosphorylation	curated
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	curated
R-HSA-9769739	Regulation of clotting cascade	curated
R-HSA-445989	TAK1-dependent IKK and NF-kappa-B activation	curated
R-HSA-933542	TRAF6 mediated NF-kB activation	curated
R-HSA-844456	The NLRP3 inflammasome	curated
R-HSA-9664424	Cell recruitment (pro-inflammatory response) ⚕	—
R-HSA-9734009	Defective Intrinsic Pathway for Apoptosis ⚕	—
R-HSA-1643685	Disease ⚕	—
R-HSA-9645723	Diseases of programmed cell death ⚕	—
R-HSA-5663205	Infectious disease ⚕	—
R-HSA-9658195	Leishmania infection ⚕	—
R-HSA-8863678	Neurodegenerative Diseases ⚕	—
R-HSA-9824443	Parasitic Infection Pathways ⚕	—
R-HSA-879415	Advanced glycosylation endproduct receptor signaling	electronic
R-HSA-373076	Class A/1 (Rhodopsin-like receptors)	—
R-HSA-1280215	Cytokine Signaling in Immune system	—
R-HSA-168928	DDX58/IFIH1-mediated induction of interferon-alpha/beta	—
R-HSA-1474244	Extracellular matrix organization	—
R-HSA-388396	GPCR downstream signalling	—
R-HSA-500792	GPCR ligand binding	—
R-HSA-109582	Hemostasis	—
R-HSA-168256	Immune System	—
R-HSA-622312	Inflammasomes	—
R-HSA-168249	Innate Immune System	—
R-HSA-9609523	Insertion of tail-anchored proteins into the endoplasmic reticulum membrane	electronic
R-HSA-446652	Interleukin-1 family signaling	—
R-HSA-9020702	Interleukin-1 signaling	—
R-HSA-199991	Membrane Trafficking	—
R-HSA-392499	Metabolism of proteins	—
R-HSA-975871	MyD88 cascade initiated on plasma membrane	—
R-HSA-975155	MyD88 dependent cascade initiated on endosome	—
R-HSA-166166	MyD88-independent TLR4 cascade	—
R-HSA-166058	MyD88:MAL(TIRAP) cascade initiated on plasma membrane	—
R-HSA-168643	Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	—
R-HSA-375276	Peptide ligand-binding receptors	—
R-HSA-76002	Platelet activation, signaling and aggregation	—
R-HSA-597592	Post-translational protein modification	—
R-HSA-9609507	Protein localization	—
R-HSA-76005	Response to elevated platelet cytosolic Ca2+	—
R-HSA-162582	Signal Transduction	—
R-HSA-372790	Signaling by GPCR	—
R-HSA-449147	Signaling by Interleukins	—
R-HSA-975138	TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	—
R-HSA-937061	TRIF (TICAM1)-mediated TLR4 signaling	—
R-HSA-168142	Toll Like Receptor 10 (TLR10) Cascade	—
R-HSA-181438	Toll Like Receptor 2 (TLR2) Cascade	—
R-HSA-168164	Toll Like Receptor 3 (TLR3) Cascade	—

MSigDB gene sets: 1131 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, VALK_AML_WITH_FLT3_ITD, REACTOME_DDX58_IFIH1_MEDIATED_INDUCTION_OF_INTERFERON_ALPHA_BETA, GOBP_CELLULAR_RESPONSE_TO_LIPOPROTEIN_PARTICLE_STIMULUS, GOBP_DENDRITE_DEVELOPMENT, GOBP_G_PROTEIN_COUPLED_RECEPTOR_INTERNALIZATION, GOBP_MEMORY, GOBP_REGULATION_OF_CELL_ACTIVATION, RNGTGGGC_UNKNOWN, VERHAAK_AML_WITH_NPM1_MUTATED_DN, FXR_IR1_Q6, RRAGTTGT_UNKNOWN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPONSE_TO_ETHANOL, GOBP_NEURON_RECOGNITION

GO Biological Process (76): microglial cell activation (GO:0001774), astrocyte activation involved in immune response (GO:0002265), regulation of translation (GO:0006417), calcium ion transport (GO:0006816), intracellular copper ion homeostasis (GO:0006878), endocytosis (GO:0006897), cell adhesion (GO:0007155), Notch signaling pathway (GO:0007219), axonogenesis (GO:0007409), central nervous system development (GO:0007417), learning or memory (GO:0007611), learning (GO:0007612), mating behavior (GO:0007617), locomotory behavior (GO:0007626), axo-dendritic transport (GO:0008088), negative regulation of cell population proliferation (GO:0008285), adult locomotory behavior (GO:0008344), visual learning (GO:0008542), response to lead ion (GO:0010288), regulation of gene expression (GO:0010468), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), microglia development (GO:0014005), axon midline choice point recognition (GO:0016199), neuron remodeling (GO:0016322), dendrite development (GO:0016358), regulation of Wnt signaling pathway (GO:0030111), extracellular matrix organization (GO:0030198), neuron projection development (GO:0031175), positive regulation of synaptic transmission, cholinergic (GO:0032224), positive regulation of chemokine production (GO:0032722), positive regulation of interleukin-1 beta production (GO:0032731), positive regulation of interleukin-6 production (GO:0032755), positive regulation of tumor necrosis factor production (GO:0032760), ionotropic glutamate receptor signaling pathway (GO:0035235), swimming behavior (GO:0036269), regulation of multicellular organism growth (GO:0040014), regulation of neuron apoptotic process (GO:0043523), response to ethanol (GO:0045471), positive regulation of glycolytic process (GO:0045821), positive regulation of mitotic cell cycle (GO:0045931), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of JNK cascade (GO:0046330), astrocyte activation (GO:0048143), regulation of long-term neuronal synaptic plasticity (GO:0048169), collateral sprouting in absence of injury (GO:0048669), positive regulation of inflammatory response (GO:0050729), regulation of synapse structure or activity (GO:0050803), synapse organization (GO:0050808), positive regulation of calcium-mediated signaling (GO:0050850), cognition (GO:0050890), positive regulation of protein metabolic process (GO:0051247), positive regulation of ERK1 and ERK2 cascade (GO:0070374), response to interleukin-1 (GO:0070555), cellular response to copper ion (GO:0071280), cellular response to manganese ion (GO:0071287), cellular response to cAMP (GO:0071320), cellular response to norepinephrine stimulus (GO:0071874), modulation of excitatory postsynaptic potential (GO:0098815), NMDA selective glutamate receptor signaling pathway (GO:0098989)

+16 more (showing top 60).

GO Molecular Function (17): DNA binding (GO:0003677), serine-type endopeptidase inhibitor activity (GO:0004867), signaling receptor binding (GO:0005102), heparin binding (GO:0008201), peptidase activator activity (GO:0016504), enzyme binding (GO:0019899), signaling receptor activator activity (GO:0030546), identical protein binding (GO:0042802), transition metal ion binding (GO:0046914), receptor ligand activity (GO:0048018), PTB domain binding (GO:0051425), growth factor receptor binding (GO:0070851), protein serine/threonine kinase binding (GO:0120283), protein binding (GO:0005515), peptidase inhibitor activity (GO:0030414), metal ion binding (GO:0046872), molecular function activator activity (GO:0140677)

GO Cellular Component (43): extracellular region (GO:0005576), nuclear envelope lumen (GO:0005641), cytoplasm (GO:0005737), mitochondrial inner membrane (GO:0005743), endosome (GO:0005768), early endosome (GO:0005769), endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788), Golgi apparatus (GO:0005794), Golgi lumen (GO:0005796), Golgi-associated vesicle (GO:0005798), cytosol (GO:0005829), plasma membrane (GO:0005886), clathrin-coated pit (GO:0005905), cell surface (GO:0009986), membrane (GO:0016020), axon (GO:0030424), dendrite (GO:0030425), platelet alpha granule lumen (GO:0031093), early endosome membrane (GO:0031901), endosome lumen (GO:0031904), trans-Golgi network membrane (GO:0032588), synaptic cleft (GO:0043083), dendritic spine (GO:0043197), dendritic shaft (GO:0043198), perikaryon (GO:0043204), signaling receptor complex (GO:0043235), main axon (GO:0044304), membrane raft (GO:0045121), synapse (GO:0045202), perinuclear region of cytoplasm (GO:0048471), recycling endosome (GO:0055037), extracellular exosome (GO:0070062), astrocyte projection (GO:0097449), neuronal dense core vesicle (GO:0098992), amyloid-beta complex (GO:0106003), growth cone lamellipodium (GO:1990761), growth cone filopodium (GO:1990812), nucleus (GO:0005634), growth cone (GO:0030426), platelet alpha granule (GO:0031091), cytoplasmic vesicle (GO:0031410), neuron projection (GO:0043005)

Reactome top-level categories

22 top-level categories:

Category	Pathways
Metabolism of proteins	3
GPCR downstream signalling	2
Response to elevated platelet cytosolic Ca2+	1
Extracellular matrix organization	1
trans-Golgi Network Vesicle Budding	1
Peptide ligand-binding receptors	1
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	1
Toll Like Receptor 3 (TLR3) Cascade	1
Interleukin-1 signaling	1
TRIF (TICAM1)-mediated TLR4 signaling	1
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	1
MyD88 cascade initiated on plasma membrane	1
Inflammasomes	1
Innate Immune System	1
Neurodegenerative Diseases	1
Post-translational protein modification	1
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1
Protein localization	1
Cell recruitment (pro-inflammatory response)	1
Coagulation pathway	1
Defects of Coagulation cascade	1
Defects of contact activation system and kallikrein-kinin system	1

GO top-level categories

showing 60 of 82 GO namespaces:

Category	Terms
cellular anatomical structure	5
endomembrane system	4
neuron projection	3
protein binding	3
cytoplasm	3
behavior	2
peptidase activity	2
peptidase regulator activity	2
signaling receptor binding	2
cytoplasmic vesicle	2
intracellular membrane-bounded organelle	2
intracellular organelle lumen	2
membrane	2
leukocyte activation involved in inflammatory response	1
macrophage activation	1
glial cell activation	1
cell activation involved in immune response	1
immune response	1
astrocyte activation	1
translation	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
metal ion transport	1
intracellular monoatomic cation homeostasis	1
copper ion homeostasis	1
vesicle budding from membrane	1
membrane invagination	1
import into cell	1
cellular process	1
cell surface receptor signaling pathway	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
axon development	1
nervous system development	1
system development	1
animal gross anatomical part developmental process	1
cognition	1
learning or memory	1
reproductive behavior	1
transport along microtubule	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
locomotory behavior	1
adult behavior	1
visual behavior	1
associative learning	1
response to metal ion	1
gene expression	1
regulation of macromolecule biosynthetic process	1
nucleic acid binding	1
serine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
glycosaminoglycan binding	1
sulfur compound binding	1
enzyme activator activity	1
signaling receptor regulator activity	1
signaling receptor activity	1
molecular function activator activity	1
metal ion binding	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 60 of 137 annotations. The rest are phylogenetic / computational / electronic (IEA).

60 experimentally-supported GO terms:

GO term	NS	Evidence
amyloid fibril formation	BP	mutant phenotype
astrocyte activation	BP	genetic interaction
astrocyte activation involved in immune response	BP	genetic interaction
cellular response to amyloid-beta	BP	direct assay
learning	BP	mutant phenotype
learning or memory	BP	mutant phenotype
microglia development	BP	genetic interaction
microglial cell activation	BP	genetic interaction
modulation of excitatory postsynaptic potential	BP	genetic interaction
negative regulation of cell population proliferation	BP	direct assay
negative regulation of gene expression	BP	genetic interaction
negative regulation of long-term synaptic potentiation	BP	genetic interaction
neuron projection maintenance	BP	genetic interaction
positive regulation of ERK1 and ERK2 cascade	BP	genetic interaction
positive regulation of JNK cascade	BP	genetic interaction
positive regulation of T cell migration	BP	mutant phenotype
positive regulation of amyloid fibril formation	BP	mutant phenotype
positive regulation of calcium-mediated signaling	BP	genetic interaction
positive regulation of chemokine production	BP	genetic interaction
positive regulation of gene expression	BP	mutant phenotype
positive regulation of glycolytic process	BP	genetic interaction
positive regulation of inflammatory response	BP	mutant phenotype
positive regulation of interleukin-1 beta production	BP	genetic interaction
positive regulation of interleukin-6 production	BP	genetic interaction
positive regulation of long-term synaptic potentiation	BP	genetic interaction
positive regulation of non-canonical NF-kappaB signal transduction	BP	mutant phenotype
positive regulation of protein metabolic process	BP	mutant phenotype
positive regulation of synaptic transmission, cholinergic	BP	direct assay
positive regulation of transcription by RNA polymerase II	BP	genetic interaction
positive regulation of tumor necrosis factor production	BP	genetic interaction
regulation of gene expression	BP	mutant phenotype
regulation of long-term neuronal synaptic plasticity	BP	genetic interaction
regulation of presynapse assembly	BP	direct assay
regulation of spontaneous synaptic transmission	BP	genetic interaction
synapse organization	BP	genetic interaction
Golgi apparatus	CC	direct assay
amyloid-beta complex	CC	direct assay
cell surface	CC	direct assay
cytoplasm	CC	direct assay
dendrite	CC	direct assay
dendritic shaft	CC	direct assay
dendritic spine	CC	direct assay
early endosome	CC	direct assay
early endosome membrane	CC	direct assay
endoplasmic reticulum	CC	direct assay
endosome	CC	direct assay
extracellular exosome	CC	high-throughput assay
membrane raft	CC	direct assay
nuclear envelope lumen	CC	direct assay
perinuclear region of cytoplasm	CC	direct assay
plasma membrane	CC	direct assay
signaling receptor complex	CC	direct assay
synapse	CC	direct assay
PTB domain binding	MF	physical interaction
enzyme binding	MF	physical interaction
identical protein binding	MF	physical interaction
protein serine/threonine kinase binding	MF	physical interaction
receptor ligand activity	MF	direct assay
serine-type endopeptidase inhibitor activity	MF	direct assay
signaling receptor binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 6,488 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
APP	PSEN1	P49768	982
APP	BACE1	P56817	975
APP	APOE	P02649	956
APP	PSEN2	P49810	949
APP	MAPT	P10636	947
APP	SNCA	P37840	919
APP	NCSTN	Q92542	899
APP	APBB1	O00213	898
APP	PSENEN	Q9NZ42	887
APP	APH1A	Q96BI3	882
APP	ADAM10	O14672	869
APP	PRNP	P04156	866
APP	IDE	P14735	862
APP	MMEL1	Q495T6	861
APP	MME	P08473	830

IntAct

Human interaction partners of APP in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records, in a sample of 1,094 of 1,656 records).

showing 30 of 338 partners by confidence:

Partner	Interaction type	MIscore	Records
APBB1	physical association	0.910	11
BACE1	protein cleavage	0.870	8
APBB3	physical association	0.850	4
APBB2	association	0.830	5
MAPK8IP1	physical association	0.780	4
PRNP	physical association	0.770	6
ITM2B	physical association	0.770	5
HSD17B10	physical association	0.750	9
MAPT	phosphorylation reaction	0.750	9
APOA1	physical association	0.750	8
CALR	association	0.740	5
APBA3	physical association	0.740	3
APBA1	physical association	0.730	3
TGFB2	proximity	0.700	6
PDIA3	physical association	0.700	5
UCHL1	physical association	0.700	4
SORL1	physical association	0.690	5
APBA2	direct interaction	0.690	2
SHC3	physical association	0.680	5
PSEN2	physical association	0.680	4
JUN	physical association	0.680	3
ACTB	physical association	0.670	6
HSPA8	physical association	0.670	6
STXBP1	physical association	0.670	6
CRYAB	association	0.670	5
HSP90AA1	physical association	0.670	3
HSPA5	physical association	0.670	3
PGAM1	physical association	0.670	3
PPIA	physical association	0.670	3
TUBB	physical association	0.670	3

BioGRID (2,974 interactions; top human partners by supporting records in a sample of 600 records): CLU (FRET; 6 records), LRPPRC (Co-fractionation; 5 records), APBA1 (Affinity Capture-Western; 4 records), APBA2 (Affinity Capture-Western; 4 records), APBB1 (Affinity Capture-Western; 4 records), FBLN1 (Affinity Capture-Western; 4 records), GRIN1 (Affinity Capture-Western; 4 records), GSAP (Affinity Capture-Western; 4 records), NGFR (Affinity Capture-Western; 4 records), TMEM30A (Affinity Capture-MS; 4 records), APBA3 (Affinity Capture-MS; 3 records), APBB2 (Affinity Capture-MS; 3 records), FLRT3 (Two-hybrid; 3 records), GRIN2A (Affinity Capture-Western; 3 records), GRIN2B (Affinity Capture-Western; 3 records)

SIGNOR signaling

showing 32 of 56 signaling interactions:

A	Effect	B	Mechanism
MAPK8	up-regulates	APP	phosphorylation
APP	up-regulates	GSK3A
Avagacestat	down-regulates	APP	“chemical inhibition”
DAPT	down-regulates	APP	“chemical inhibition”
471905-41-6	down-regulates	APP	“chemical inhibition”
PAFAH1B2	up-regulates	APP
MAPK10	up-regulates	APP	phosphorylation
(2S)-2-hydroxy-3-methyl-N-[(2S)-1-[[(5S)-3-methyl-4-oxo-2,5-dihydro-1H-3-benzazepin-5-yl]amino]-1-oxopropan-2-yl]butanamide	down-regulates	APP	“chemical inhibition”
gamma-secretase	“up-regulates activity”	APP	cleavage
APP	“up-regulates activity”	NAE1	binding
APP	up-regulates	Amyloid_fibril_formation
CTCF	“up-regulates quantity by expression”	APP	“transcriptional regulation”
PITRM1	“down-regulates activity”	APP	cleavage
CDK5RAP2	“up-regulates quantity by stabilization”	APP	phosphorylation
PLD3	“up-regulates quantity”	APP	binding
BACE1	“up-regulates activity”	APP	cleavage
BACE2	“up-regulates activity”	APP	cleavage
ABCA7	“down-regulates quantity”	APP	relocalization
FYN	“up-regulates quantity”	APP	phosphorylation
SYVN1	“down-regulates quantity by destabilization”	APP	ubiquitination
PRKN	“down-regulates quantity”	APP	ubiquitination
PLK2	“up-regulates activity”	APP	phosphorylation
DAPK1	“up-regulates quantity”	APP	phosphorylation
ROCK2	“up-regulates quantity”	APP	phosphorylation
CDK2	“down-regulates quantity by destabilization”	APP	phosphorylation
CDK4	“down-regulates quantity by destabilization”	APP	phosphorylation
CDK5	unknown	APP	phosphorylation
GSK3B	unknown	APP	phosphorylation
CTSD	“down-regulates quantity by destabilization”	APP	cleavage
CTSD	“up-regulates activity”	APP	cleavage
CASP6	“up-regulates activity”	APP	cleavage
ADAM17	“up-regulates activity”	APP	cleavage

Protein complexes (CORUM) (22)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

22 complexes by size:

Complex	Subunits	Members
★ APP(AICD)-FE65-TIP60-MED12-MED4 complex (incomplete Mediator complex)	5	MED4, APBB1, APP, KAT5, MED12
★ APP(AICD)-MED12-MED23-MED4 complex (incomplete Mediator complex)	4	APP, MED12, MED23, MED4
★ APP-Abeta42-VDAC1 complex	3	APP, VDAC1
★ APBB1-APP-KAT5 complex	3	APBB1, APP, KAT5
★ APP-TIMM23-TOMM40 supercomplex, mitochondrial	3	APP, TIMM23, TOMM40
★ Abeta(monomer)-APOE complex	2	APOE, APP
★ Abeta(dimer)-APOE complex	2	APOE, APP
★ Abeta(trimer)-APOE complex	2	APP, APOE
★ APP-TOMM40 complex, mitochondrial	2	APP, TOMM40
★ APP-TIMM23 complex, mitochondrial	2	APP, TIMM23
★ APP-TNFRSF21 complex	2	APP, TNFRSF21
★ APP-PSEN1 complex	2	APP, PSEN1
★ APP-PSEN2 complex	2	APP, PSEN2
★ APP(AICD)-FOXO3 complex	2	APP, FOXO3
★ APP(AICD)-FOXO1 complex	2	FOXO1, APP
★ APP(AICD)-FOXO4 complex	2	APP, FOXO4
★ Abeta-BCHE complex	2	APP, BCHE
★ Abeta-ACHE complex	2	ACHE, APP
★ APBB1-APP(AICD) complex	2	APBB1, APP
★ APBB2-APP complex	2	APBB2, APP
★ APP(CTF-C99)-NCSTN complex	2	APP, NCSTN
★ APP(CTF-C83)-NCSTN complex	2	NCSTN, APP

Ligand–receptor pairs (CellPhoneDB) (6)

Curated ligand–receptor partners (cell-cell communication), distinct from the protein–protein interactions above.

6 ligand–receptor pairs:

Partner	This gene’s role	Signaling class
TREM2;TYROBP	ligand	Signaling by Amyloid-beta precursor protein
SORL1	ligand	Signaling by Amyloid-beta precursor protein
CD74	ligand	Signaling by Amyloid-beta precursor protein
TNFRSF21	ligand	Signaling by Amyloid-beta precursor protein
PLXNA4	ligand	Signaling by Amyloid-beta precursor protein
FPR2	ligand	Signaling by Amyloid-beta precursor protein

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 338 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
NRIF signals cell death from the nucleus	9	22.5×	8e-09
Role of LAT2/NTAL/LAB on calcium mobilization	7	14.7×	1e-05
DARPP-32 events	8	13.3×	5e-06
CD209 (DC-SIGN) signaling	7	12.7×	3e-05
Signalling to ERKs	6	12.6×	1e-04
Rap1 signalling	5	12.5×	5e-04
Advanced glycosylation endproduct receptor signaling	5	12.5×	5e-04
Signalling to RAS	5	11.7×	6e-04

GO biological processes:

GO term	Partners	Fold	FDR
astrocyte activation	6	18.0×	6e-05
cellular response to amyloid-beta	14	16.6×	7e-11
amyloid fibril formation	9	16.4×	4e-07
positive regulation of superoxide anion generation	6	16.1×	1e-04
membrane protein ectodomain proteolysis	8	15.7×	4e-06
protein refolding	8	15.1×	5e-06
response to amyloid-beta	5	15.0×	7e-04
response to lead ion	5	14.2×	9e-04

Disease & clinical

Genetic variants

Variant evidence for APP: 652 ClinVar records (32 pathogenic / likely pathogenic); 7 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

652 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	23
Likely pathogenic	9
Uncertain significance	281
Likely benign	194
Benign	69

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 32 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
18088	NM_000484.4(APP):c.2149G>A (p.Val717Ile)	Pathogenic	criteria provided, multiple submitters, no conflicts	12
18093	NM_000484.4(APP):c.2010_2011inv (p.Lys670_Met671delinsAsnLeu)	Pathogenic	criteria provided, multiple submitters, no conflicts	6
18101	NM_000484.4(APP):c.2080G>A (p.Asp694Asn)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
18089	NM_000484.4(APP):c.2149G>T (p.Val717Phe)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
18102	NM_000484.4(APP):c.2140A>G (p.Thr714Ala)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
18087	NM_000484.4(APP):c.2077G>C (p.Glu693Gln)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
1457308	NM_000484.4(APP):c.2145_2146delinsTG (p.Ile716Val)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
2498894	NM_000484.4(APP):c.2146A>T (p.Ile716Phe)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
18094	NM_000484.4(APP):c.2137G>A (p.Ala713Thr)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	9
18090	NM_000484.4(APP):c.2150T>G (p.Val717Gly)	Pathogenic	criteria provided, single submitter	3
18096	NM_000484.4(APP):c.2146A>G (p.Ile716Val)	Pathogenic	criteria provided, single submitter	3
18099	NM_000484.4(APP):c.2077G>A (p.Glu693Lys)	Pathogenic	criteria provided, single submitter	3
18100	NM_000484.4(APP):c.2141C>T (p.Thr714Ile)	Pathogenic	criteria provided, single submitter	3
18105	NM_000484.4(APP):c.2149G>C (p.Val717Leu)	Pathogenic	criteria provided, single submitter	3
98240	NM_000484.4(APP):c.2147T>C (p.Ile716Thr)	Pathogenic	criteria provided, single submitter	2

Per-variant reference — Sugi Variant

Explore APP’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 40 predictions of 2,081):

Position(s)	Effect	Δscore	Sites
21:25881772–25881773	acceptor_loss	1.0000	4
21:25891720–25891721	donor_loss	1.0000	5
21:25891869–25891870	acceptor_gain	1.0000	2
21:25891869–25891870	acceptor_loss	1.0000	4
21:25897571–25897572	donor_loss	1.0000	4
21:25911739–25911740	donor_loss	1.0000	5
21:25954588–25954589	donor_loss	1.0000	5
21:25954690–25954691	acceptor_loss	1.0000	4
21:25955625–25955626	donor_loss	1.0000	5
21:25955757	acceptor_loss	1.0000	2

AlphaMissense

2,171 missense substitutions predicted likely pathogenic (of 5,117 scored), across 476 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M752	9	0.980	1.000
M406	9	0.951	0.997
M170	9	0.910	0.996
M410	9	0.907	0.990
H457	8	0.999	1.000
H514	8	0.999	1.000
H507	8	0.998	0.999
N759	8	0.998	1.000
N329	8	0.997	1.000
H388	8	0.997	0.999
H511	8	0.997	1.000
D504	8	0.995	0.999
F331	8	0.993	1.000
H533	8	0.992	0.997
F391	8	0.987	1.000
F135	8	0.981	1.000
F765	8	0.981	0.998
F319	8	0.979	0.998
D519	8	0.977	0.999
S124	8	0.972	0.999

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	8.44e-09
Kidney Renal Clear Cell Carcinoma (validation)	favorable	1.85e-05

Disease associations

OMIM: gene MIM:104760 | disease phenotypes: MIM:104300, MIM:605714

GenCC curated gene-disease

9 curated gene-disease records:

Disease	Classification	Inheritance	Records
Alzheimer disease type 1	Strong	Autosomal dominant	2
cerebral amyloid angiopathy, APP-related	Strong	Autosomal dominant	2
ABeta amyloidosis, dutch type	Supportive	Autosomal dominant
early-onset autosomal dominant Alzheimer disease	Supportive	Autosomal dominant
ABetaL34V amyloidosis	Supportive	Autosomal dominant
ABeta amyloidosis, Iowa type	Supportive	Autosomal dominant
ABeta amyloidosis, Italian type	Supportive	Autosomal dominant
ABetaA21G amyloidosis	Supportive	Autosomal dominant
ABeta amyloidosis, Arctic type	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

1 validity classifications:

Disease	Classification	Inheritance
cerebral amyloid angiopathy, APP-related	Definitive	AD

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (5 panels, 5 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

5 panels:

Panel	Rating
Adult-onset neurological disorders	green
Early onset dementia (encompassing fronto-temporal dementia and prion disease)	green
Familial cerebral small vessel disease	green
Leukodystrophy, adult onset	green
Neurodegenerative disorders, adult onset	green

Mondo (10): Alzheimer disease type 1 (MONDO:0007088), Alzheimer disease (MONDO:0004975), cerebral amyloid angiopathy, APP-related (MONDO:0011583), ABeta amyloidosis, dutch type (MONDO:0015033), ABetaA21G amyloidosis (MONDO:0017948), ABeta amyloidosis, Arctic type (MONDO:0017949), ABeta amyloidosis, Italian type (MONDO:0017947), ABeta amyloidosis, Iowa type (MONDO:0017946), early-onset autosomal dominant Alzheimer disease (MONDO:0015140), ABetaL34V amyloidosis (MONDO:0017945)

Orphanet (9): Early-onset autosomal dominant Alzheimer disease (Orphanet:1020), ABeta amyloidosis, Dutch type (Orphanet:100006), ABetaL34V amyloidosis (Orphanet:324703), ABeta amyloidosis, Iowa type (Orphanet:324708), ABeta amyloidosis, Italian type (Orphanet:324713), ABetaA21G amyloidosis (Orphanet:324718), ABeta amyloidosis, Arctic type (Orphanet:324723), Hereditary cerebral amyloid angiopathy (Orphanet:85458), NON RARE IN EUROPE: Alzheimer disease (Orphanet:238616)

HPO phenotypes

55 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000504	Abnormality of vision
HP:0000657	Oculomotor apraxia
HP:0000708	Atypical behavior
HP:0000713	Agitation
HP:0000726	Dementia
HP:0000734	Disinhibition
HP:0000738	Hallucinations
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001259	Coma
HP:0001263	Global developmental delay
HP:0001268	Mental deterioration
HP:0001276	Hypertonia
HP:0001288	Gait disturbance
HP:0001289	Confusion
HP:0001297	Stroke
HP:0001300	Parkinsonism
HP:0001336	Myoclonus
HP:0001342	Cerebral hemorrhage
HP:0002015	Dysphagia
HP:0002076	Migraine
HP:0002120	Cerebral cortical atrophy
HP:0002138	Subarachnoid hemorrhage
HP:0002185	Neurofibrillary tangles
HP:0002186	Apraxia
HP:0002315	Headache
HP:0002354	Memory impairment
HP:0002373	Febrile seizure (within the age range of 3 months to 6 years)
HP:0002381	Aphasia
HP:0002423	Long-tract sign
HP:0002463	Language impairment
HP:0002511	Alzheimer disease
HP:0002514	Cerebral calcification
HP:0002637	Cerebral ischemia
HP:0003401	Paresthesia
HP:0003474	Somatic sensory dysfunction
HP:0003581	Adult onset
HP:0003584	Late onset
HP:0003596	Middle age onset
HP:0003791	Deposits immunoreactive to beta-amyloid protein
HP:0004938	Tortuous cerebral arteries
HP:0004968	Recurrent cerebral hemorrhage
HP:0010525	Finger agnosia
HP:0010526	Dysgraphia
HP:0011446	Abnormality of mental function
HP:0011695	Cerebellar hemorrhage
HP:0011970	Cerebral amyloid angiopathy
HP:0012433	Abnormal social behavior
HP:0012759	Neurodevelopmental abnormality
HP:0030219	Semantic dementia
HP:0100613	Death in early adulthood
HP:0100659	Abnormal cerebral vascular morphology
HP:0410054	Decreased circulating GABA concentration

GWAS associations

7 associations:

Study	Trait	p-value
GCST012182_4	Alzheimer’s disease	1e-11
GCST006279_3	Cerebrospinal fluid α-synuclein levels	2e-7
GCST90011770_79	Glaucoma (primary open-angle)	3e-7
GCST009306_7	Spatial processing	2e-6
GCST003082_7	Longitudinal change in brain amyloid plaque burden	3e-6
GCST90011768_22	Glaucoma (primary open-angle)	7e-6
GCST011743_86	HDL cholesterol levels in HIV infection	8e-6

EFO canonical traits (from GWAS)

4 canonical traits:

EFO ID	Trait name
EFO:0007646	amyloid plaque accumulation rate
EFO:0009323	alpha synuclein measurement
EFO:0008354	cognitive function measurement
EFO:0004612	high density lipoprotein cholesterol measurement

MeSH disease descriptors

2 disease descriptors:

Descriptor	Name	Tree numbers
D000544	Alzheimer Disease	C10.228.140.380.100; C10.574.945.249; F03.615.400.100
C536594	Alzheimer disease type 1 *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2487 (SINGLE PROTEIN)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the APP protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

13 curated-mechanism drugs:

Drug	Modality	Max phase
ADUCANUMAB	Antibody	4
DONANEMAB	Antibody	4
LECANEMAB	Antibody	4
BAPINEUZUMAB	Antibody	3
CRENEZUMAB	Antibody	3
GANTENERUMAB	Antibody	3
SOLANEZUMAB	Antibody	3
TRAMIPROSATE	Small molecule	3
VALILTRAMIPROSATE	Small molecule	3
AMILOMOTIDE	Protein	2
GSK933776	Unknown	2
PONEZUMAB	Antibody	2
VANUTIDE CRIDIFICAR	Protein	2

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,397,231 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

40 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL682	AMODIAQUINE	4	7,237
CHEMBL723	CARVEDILOL	4	30,479
CHEMBL76	CHLOROQUINE	4	59,347
CHEMBL497	CLIOQUINOL	4	13,056
CHEMBL502	DONEPEZIL	4	43,884
CHEMBL566752	FLORBETABEN F18	4	793
CHEMBL1908919	FLORBETAPIR	4	720
CHEMBL1774461	FLORBETAPIR F 18	4	415
CHEMBL579205	FLUTEMETAMOL	4	334
CHEMBL2042122	FLUTEMETAMOL F 18	4	287
CHEMBL64894	GENTIAN VIOLET	4	112,306
CHEMBL405110	METHYLENE BLUE ANHYDROUS	4	114,909
CHEMBL191083	METHYLENE BLUE CATION	4	7,859
CHEMBL573	NIACIN	4	355,192
CHEMBL986	RETINOL	4	278,566
CHEMBL95	TACRINE	4	35,550
CHEMBL38	TRETINOIN	4	195,980
CHEMBL149082	TRAMIPROSATE	3	8,405
CHEMBL145	CAFFEIC ACID	3	36,727
CHEMBL140	CURCUMIN	3	95,185
CHEMBL858	EDETIC ACID	3
CHEMBL297453	EPIGALOCATECHIN GALLATE	3
CHEMBL2048308	FLUTAFURANOL	3
CHEMBL3989948	LANABECESTAT	3
CHEMBL50	QUERCETIN	3
CHEMBL165	RESVERATROL	3
CHEMBL583912	(-)-EPICATECHIN	2
CHEMBL2364601	AFTOBETIN	2
CHEMBL3348861	AMPELOPSIN	2
CHEMBL284616	CHLOROGENIC ACID	2
CHEMBL6246	ELLAGIC ACID	2
CHEMBL31574	FISETIN	2
CHEMBL279014	LUCANTHONE	2
CHEMBL151	LUTEOLIN	2
CHEMBL289556	OMAPATRILAT	2
CHEMBL1368322	PARAROSANILINE	2
CHEMBL207456	PITTSBURGH COMPOUND B	2
CHEMBL93124	PITTSBURGH COMPOUND B UNLABELLED	2
CHEMBL468154	SCYLLITOL	2
CHEMBL150	KAEMPFEROL	1

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1828 measured of 1947 human assays (2068 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
1-[4-(3-fluoropropoxy)-3-methoxyphenyl]-5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-1,4,6-heptatrien-3-one	KI	0.07 nM
US10231967, Example 122	IC50	0.1 nM	US-10231967: Compounds and their use as BACE inhibitors
(trans,trans)-1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene	KI	0.11 nM
5-[2-bromo-4-(3-carboxy-4-hydroxyphenethyl)phenethyl]-2-hydroxybenzoic acid	KI	0.13 nM
US8865911, 114	IC50	0.14 nM	US-10231967: Compounds and their use as BACE inhibitors
5-(Biphenyl-4-ylazo)-bis (2-hydroxy-benzoic acid)(Chrysamine G)	KI	0.14 nM
US10231967, Example 94-Isomer-1	IC50	0.17 nM	US-10231967: Compounds and their use as BACE inhibitors
5-[2-{4-[2-(3-carboxy-4-methoxyphenyl)-(E)-1-ethenyl]-2-iodophenyl}-(E)-1-ethenyl]-2-methoxybenzoic acid	KI	0.17 nM
5-[2-bromo-4-(3-carboxy-4-hydroxyphenethyl)phenethyl]-2-hydroxybenzoic acid	KI	0.19 nM
CHEMBL1774642	KI	0.2 nM
CHEMBL607562	KD	0.21 nM
N-{3-[(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino]propyl}-5-(1,2-dithiolan-3-yl)pentanamide	IC50	0.25 nM
US10231967, Example 125	IC50	0.26 nM	US-10231967: Compounds and their use as BACE inhibitors
US8865911, 92 Isomer 2	IC50	0.27 nM	US-10231967: Compounds and their use as BACE inhibitors
5-[2-bromo-4-(3-carboxy-4-hydroxyphenethyl)phenethyl]-2-hydroxybenzoic acid	KI	0.27 nM
1-((2R,6S)-1-(4-chlorophenylsulfonyl)-6-(3,5-difluorophenyl)piperidin-2-yl)cyclopropyl 4-(piperidin-1-yl)piperidine-1-carboxylate	IC50	0.3 nM
CHEMBL1774643	KI	0.3 nM
US8865911, 20t	IC50	0.36 nM	US-10231967: Compounds and their use as BACE inhibitors
2,7-bis(6-(ethyl(2-methoxybenzyl)amino)hexyl)benzo[lmn][3,8]phenanthroline-1,3,6,8(2H,7H)-tetraone	IC50	0.37 nM
US10231967, Example 68-Isomer-1	IC50	0.38 nM	US-10231967: Compounds and their use as BACE inhibitors
(R,E)-2-(3-((2-fluoroethoxy)methyl)-4-(pyrimidin-2-yl)piperazin-1-yl)-5-(2-(6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl)vinyl)pyrimidine	KI	0.42 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R)-2-(2-((2-fluoroethoxy)methyl)-4-(5-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)ethynyl)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazine	KI	0.449 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
N,N-dimethyl-4-[2-(6-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethynyl]aniline	KD	0.49 nM	US-10906900: Compounds for using in imaging and particularly for the diagnosis of neurodegenerative diseases
(R,E)-5-(2-(6-(1H-imidazol-1-yl)pyridin-3-yl)vinyl)-2-(3-((2-fluoroethoxy)methyl)-4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidine	KI	0.5 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-5-(2-(6-(1H-imidazol-1-yl)pyridin-3-yl)vinyl)-2-(2-(methoxymethyl)-4-(pyridin-2-yl)piperazin-1-yl)pyrimidine	KI	0.5 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-(1-(5-(2-(6-(1H-imidazol-1-yl)pyridin-3-yl)vinyl)pyrimidin-2-yl)-4-(pyrimidin-4-yl)piperazin-2-yl)methanol	KI	0.5 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-5-(2-(6-(1H-imidazol-1-yl)pyridin-3-yl)vinyl)-2-(2-((2-fluoroethoxy)methyl)-4-(pyridin-4-yl)piperazin-1-yl)pyrimidine	KI	0.5 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
1-((2-((R)-4-(5-((E)-2-(6-(1H-imidazol-1-yl)pyridin-3-yl)vinyl)pyrimidin-2-yl)-2-(methoxymethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)-3-fluoropropan-2-ol	KI	0.52 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
N,N-dimethyl-4-[2-(1H-pyrrolo[2,3-b]pyridin-2-yl)ethynyl]aniline	KD	0.53 nM	US-10906900: Compounds for using in imaging and particularly for the diagnosis of neurodegenerative diseases
US8865911, 94 Isomer 2	IC50	0.56 nM	US-10231967: Compounds and their use as BACE inhibitors
CHEMBL3314344	KD	0.56 nM
US8865911, 20e	IC50	0.57 nM	US-10231967: Compounds and their use as BACE inhibitors
(R)-2-(2-((2-fluoroethoxy)methyl)-4-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-5-yl)ethynyl)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazine	KI	0.57 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
US8865911, 100	IC50	0.59 nM	US-10231967: Compounds and their use as BACE inhibitors
US8865911, 20u	IC50	0.6 nM	US-9000182: 2H-imidazol-4-amine compounds and their use as BACE inhibitors
US8865911, 91	IC50	0.62 nM	US-10231967: Compounds and their use as BACE inhibitors
(R,E)-5-(2-(6-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)pyridin-3-yl)vinyl)-2-(3-(methoxymethyl)-4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidine	KI	0.62 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
US9000182, 9, isomer 1	IC50	0.7 nM	US-9000182: 2H-imidazol-4-amine compounds and their use as BACE inhibitors
US9000182, 11, isomer 1	IC50	0.7 nM	US-9000182: 2H-imidazol-4-amine compounds and their use as BACE inhibitors
(2S,4S)-6-(3-chlorophenyl)-5’-methyl-2-[(3R)-oxan-3-yl]spiro[2,3-dihydrochromene-4,2’-imidazole]-4’-amine	IC50	0.7 nM	US-10231967: Compounds and their use as BACE inhibitors
(R,E)-5-(2-(6-(1H-imidazol-1-yl)pyridin-3-yl)vinyl)-2-(3-(methoxymethyl)-4-(pyridin-2-yl)piperazin-1-yl)pyrimidine	KI	0.7 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
5-hydroxy-2-(4-methylaminophenyl)benzofuran	KI	0.7 nM
US10231967, Example 20aa	IC50	0.72 nM	US-10231967: Compounds and their use as BACE inhibitors
N,N-dimethyl-4-[2-(6-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethynyl]aniline	KD	0.73 nM	US-10906900: Compounds for using in imaging and particularly for the diagnosis of neurodegenerative diseases
US10231967, Example 72	IC50	0.76 nM	US-10231967: Compounds and their use as BACE inhibitors
US8865911, 20b	IC50	0.78 nM	US-10231967: Compounds and their use as BACE inhibitors
(R,E)-5-(5-(2-(2-(3-((2-fluoroethoxy)methyl)-4-(pyrimidin-4-yl)piperazin-1-yl)pyrimidin-5-yl)vinyl)pyridin-2-yl)oxazole	KI	0.78 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
4-[2-(6-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)ethynyl]-N,N-dimethylaniline	KD	0.79 nM	US-10906900: Compounds for using in imaging and particularly for the diagnosis of neurodegenerative diseases
US8865911, 85	IC50	0.8 nM	US-10231967: Compounds and their use as BACE inhibitors
US9000183, 6 Isomer 1	IC50	0.8 nM	US-9000183: Cyclohexane-1,2′-indene-1′,2″-imidazol compounds and their use as BACE inhibitors

ChEMBL bioactivities

1956 potent at pChembl≥5 of 2424 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.15	Ki	0.07	nM	CHEMBL384465
10.00	IC50	0.1	nM	CHEMBL2152914
9.96	Ki	0.11	nM	CHEMBL74704
9.89	Ki	0.13	nM	CHEMBL76112
9.85	Ki	0.14	nM	CHRYSAMINE G
9.85	IC50	0.14	nM	LANABECESTAT
9.80	Ki	0.16	nM	CHRYSAMINE G
9.77	Ki	0.17	nM	CHEMBL292910
9.77	IC50	0.17	nM	CHEMBL6008112
9.72	Ki	0.19	nM	CHEMBL305634
9.70	Ki	0.2	nM	CHEMBL1774642
9.68	Ki	0.208	nM	CURCUMIN
9.68	Kd	0.21	nM	CHEMBL607562
9.59	IC50	0.26	nM	CHEMBL2152915
9.57	IC50	0.27	nM	CHEMBL4111546
9.57	Ki	0.27	nM	CHEMBL74348
9.55	IC50	0.28	nM	CHEMBL2152914
9.52	IC50	0.3	nM	CHEMBL240055
9.52	IC50	0.3	nM	CHEMBL2152914
9.52	Ki	0.3	nM	CHEMBL1774643
9.44	IC50	0.36	nM	CHEMBL2152917
9.42	IC50	0.38	nM	CHEMBL5918838
9.40	Ki	0.4	nM	CHRYSAMINE G
9.30	IC50	0.5	nM	CHEMBL2152915
9.25	Kd	0.56	nM	CHEMBL3314344
9.25	IC50	0.56	nM	CHEMBL2152917
9.25	IC50	0.56	nM	CHEMBL3936953
9.24	IC50	0.57	nM	CHEMBL3965844
9.23	IC50	0.59	nM	CHEMBL3974225
9.22	IC50	0.6	nM	CHEMBL3959097
9.21	IC50	0.62	nM	CHEMBL3907727
9.20	IC50	0.63	nM	CHEMBL2152915
9.20	IC50	0.63	nM	CHEMBL3959097
9.19	IC50	0.65	nM	MRK-560
9.17	IC50	0.67	nM	CHEMBL3965844
9.15	Ki	0.7	nM	FLUTEMETAMOL F 18
9.15	Ki	0.7	nM	CHEMBL204829
9.15	IC50	0.7	nM	CHEMBL3898248
9.15	IC50	0.7	nM	CHEMBL4110988
9.15	IC50	0.7	nM	CHEMBL5773881
9.15	IC50	0.7	nM	CHEMBL6008112
9.14	IC50	0.72	nM	CHEMBL2152915
9.14	IC50	0.72	nM	CHEMBL2152918
9.14	IC50	0.72	nM	CHEMBL3974225
9.13	Ki	0.74	nM	FLUTEMETAMOL F 18
9.13	Ki	0.74	nM	FLUTEMETAMOL
9.12	IC50	0.76	nM	CHEMBL2152920
9.11	IC50	0.78	nM	CHEMBL3901045
9.10	Ki	0.8	nM	CHEMBL292910
9.10	Ki	0.8	nM	CHEMBL55401

PubChem BioAssay actives

768 with measured affinity, of 6100 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
5-[(E)-2-[3-bromo-4-[(E)-2-(3-carboxy-4-hydroxyphenyl)ethenyl]phenyl]ethenyl]-2-hydroxybenzoic acid	38551: Inhibitory activity against binding of [125I]IMSB to amyloid beta in brain	ki	0.0001	uM
5-[(Z)-2-[3-bromo-4-[(Z)-2-(3-carboxy-4-hydroxyphenyl)ethenyl]phenyl]ethenyl]-2-hydroxybenzoic acid	38551: Inhibitory activity against binding of [125I]IMSB to amyloid beta in brain	ki	0.0001	uM
5-[[4-[4-[(3-carboxy-4-hydroxyphenyl)diazenyl]phenyl]phenyl]diazenyl]-2-hydroxybenzoic acid	38550: Inhibition constant for aggregates of amyloid beta compared to [125I]IMSB	ki	0.0001	uM
(1E,4Z,6E)-7-[4-(3-fluoropropoxy)-3-methoxyphenyl]-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)hepta-1,4,6-trien-3-one	272869: Displacement of [125I]IMSB from beta amyloid protein 40	ki	0.0001	uM
5-[(E)-2-[4-[(E)-2-(3-carboxy-4-methoxyphenyl)ethenyl]-3-iodophenyl]ethenyl]-2-methoxybenzoic acid	38550: Inhibition constant for aggregates of amyloid beta compared to [125I]IMSB	ki	0.0002	uM
5-[(E)-2-[3-bromo-4-[(Z)-2-(3-carboxy-4-hydroxyphenyl)ethenyl]phenyl]ethenyl]-2-hydroxybenzoic acid	38551: Inhibitory activity against binding of [125I]IMSB to amyloid beta in brain	ki	0.0002	uM
[1-[(2R,6S)-1-(4-chlorophenyl)sulfonyl-6-(3,5-difluorophenyl)piperidin-2-yl]cyclopropyl] 4-piperidin-1-ylpiperidine-1-carboxylate	301167: Inhibition of gamma-secretase assessed as reduction of membrane A-beta-40 level	ic50	0.0003	uM
5-[(Z)-2-[3-bromo-4-[(E)-2-(3-carboxy-4-hydroxyphenyl)ethenyl]phenyl]ethenyl]-2-hydroxybenzoic acid	38551: Inhibitory activity against binding of [125I]IMSB to amyloid beta in brain	ki	0.0003	uM
1-(125I)iodo-4-[(4-methoxyphenoxy)methyl]benzene	1179998: Binding affinity to amyloid beta42 (unknown origin) after 3 hrs by gamma counting	kd	0.0006	uM
2-[3-fluoro-4-(methylamino)phenyl]-1,3-benzothiazol-6-ol	445593: Binding affinity to Beta amyloid aggregates in Alzheimer’s disease patient brain by competitive binding assay	ki	0.0007	uM
2-[4-(methylamino)phenyl]-1-benzofuran-5-ol	264125: Displacement of [125I]IMPY from beta amyloid in human corpse AD brain	ki	0.0007	uM
Flutemetamol F-18	668927: Displacement of [18F]-amyvid from amyloid-beta aggregates in alzheimer’s disease patient brain homogenates after 1 hr	ki	0.0007	uM
4-(6-bromo-1,3-benzothiazol-2-yl)-N,N-dimethylaniline	38549: Inhibition constant for amyloid beta compared to [125I]TZDM	ki	0.0008	uM
2-[4-((111C)methylamino)phenyl]-1,3-benzothiazol-6-ol	673978: Binding affinity to human amyloid beta plaque	ki	0.0008	uM
2-[4-(methylamino)phenyl]-1,3-benzothiazol-6-ol	445593: Binding affinity to Beta amyloid aggregates in Alzheimer’s disease patient brain by competitive binding assay	ki	0.0009	uM
4-(6-iodo-1,3-benzothiazol-2-yl)-N,N-dimethylaniline	38549: Inhibition constant for amyloid beta compared to [125I]TZDM	ki	0.0009	uM
N-[3-[(6R)-4-amino-2-cyano-6-methyl-7H-pyrazolo[1,5-a]pyrazin-6-yl]-4-fluorophenyl]-5-cyanopyridine-2-carboxamide	1819117: Inhibition of human amyloid beta (1 to 42) in human SKNBE2 cells expressing wild-type amyloid precursor protein hAPP695 incubated for 18 hrs by sandwich ELISA	ic50	0.0010	uM
N-[3-[(6R)-4-amino-2-cyano-6-methyl-7H-pyrazolo[1,5-a]pyrazin-6-yl]-4-fluorophenyl]-5-(difluoromethoxy)pyridine-2-carboxamide	1819117: Inhibition of human amyloid beta (1 to 42) in human SKNBE2 cells expressing wild-type amyloid precursor protein hAPP695 incubated for 18 hrs by sandwich ELISA	ic50	0.0010	uM
(E,2Z,5Z)-2-[(2E,4E)-5-[4-(dimethylamino)phenyl]penta-2,4-dienylidene]-5-[(E)-3-[4-(dimethylamino)phenyl]prop-2-enylidene]hex-3-enedinitrile	2213906: Binding affinity to amyloid beta plaques 1 to 42 (unknown origin) assessed as dissociation constant	kd	0.0010	uM
4-[(E)-2-[4-(dimethylamino)phenyl]ethenyl]phenol	254419: Inhibition constant for I-125-IMPY binding to amyloid plaques in Alzheimers disease brain homogenates	ki	0.0011	uM
4-[(E)-2-[4-(methylamino)phenyl]ethenyl]phenol	254419: Inhibition constant for I-125-IMPY binding to amyloid plaques in Alzheimers disease brain homogenates	ki	0.0012	uM
4-[2-[4-[2-(2-fluoroethoxy)ethoxy]phenyl]ethynyl]-N-methylaniline	286796: Displacement of [125I]IMPY from human beta amyloid plaque in brain homogenates	ki	0.0012	uM
N-[3-[(6R)-4-amino-2-cyano-6-methyl-7H-pyrazolo[1,5-a]pyrazin-6-yl]-4-fluorophenyl]-5-(fluoromethoxy)pyrazine-2-carboxamide	1819117: Inhibition of human amyloid beta (1 to 42) in human SKNBE2 cells expressing wild-type amyloid precursor protein hAPP695 incubated for 18 hrs by sandwich ELISA	ic50	0.0012	uM
4-(6-iodoimidazo[1,2-a]pyridin-2-yl)-N,N-dimethylaniline	445593: Binding affinity to Beta amyloid aggregates in Alzheimer’s disease patient brain by competitive binding assay	ki	0.0013	uM
4-(5-methoxy-1-benzofuran-2-yl)-N-methylaniline	264125: Displacement of [125I]IMPY from beta amyloid in human corpse AD brain	ki	0.0013	uM
N-[3-[(6R)-4-amino-2-cyano-6-methyl-7H-pyrazolo[1,5-a]pyrazin-6-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide	1819117: Inhibition of human amyloid beta (1 to 42) in human SKNBE2 cells expressing wild-type amyloid precursor protein hAPP695 incubated for 18 hrs by sandwich ELISA	ic50	0.0013	uM
4-[2-[4-(methylamino)phenyl]ethynyl]phenol	286796: Displacement of [125I]IMPY from human beta amyloid plaque in brain homogenates	ki	0.0015	uM
5-[2-[4-[2-[2-(2-fluoroethoxy)ethoxy]ethoxy]phenyl]ethynyl]-1H-indole	365222: Displacement of [125I]IMPY from beta-amyloid plaques in AD patient brain	ki	0.0015	uM
6-bromo-2-[4-(4-methylpiperazin-1-yl)phenyl]-1,3-benzothiazole	38549: Inhibition constant for amyloid beta compared to [125I]TZDM	ki	0.0016	uM
5-[(E)-2-[5-(2-fluoroethoxy)-1,3-benzoselenazol-2-yl]ethenyl]-N,N-dimethylpyrimidin-2-amine	1884928: Binding affinity to amyloid beta (1 to 42) (unknown origin) aggregates	kd	0.0016	uM
4-(6-bromo-1,3-benzothiazol-2-yl)-N-methylaniline	38663: Binding affinity for Amyloid beta 1-40 aggregates in competition with [N-methyl-3H] BTA-1.	ki	0.0017	uM
2-[6-(methylamino)-3-pyridinyl]-1,3-benzothiazol-6-ol	445593: Binding affinity to Beta amyloid aggregates in Alzheimer’s disease patient brain by competitive binding assay	ki	0.0017	uM
4-(6-methoxy-1,3-benzothiazol-2-yl)-N,N-dimethylaniline	38663: Binding affinity for Amyloid beta 1-40 aggregates in competition with [N-methyl-3H] BTA-1.	ki	0.0019	uM
4-[2-[4-[2-[2-(2-fluoroethoxy)ethoxy]ethoxy]phenyl]ethynyl]-N-methylaniline	286796: Displacement of [125I]IMPY from human beta amyloid plaque in brain homogenates	ki	0.0019	uM
4-[(E)-2-(4-iodophenyl)ethenyl]-N,N-dimethylaniline	445593: Binding affinity to Beta amyloid aggregates in Alzheimer’s disease patient brain by competitive binding assay	ki	0.0020	uM
2-[(2E,4E)-5-(1-benzylindol-5-yl)penta-2,4-dienylidene]propanedinitrile	2037033: Competitive binding affinity to amyloid beta (1 to 42) (unknown origin) assessed as inhibition constant incubated for 0.5 hrs by ThT-based fluorescence microplate reader analysis	ki	0.0020	uM
florbetaben f-18	668927: Displacement of [18F]-amyvid from amyloid-beta aggregates in alzheimer’s disease patient brain homogenates after 1 hr	ki	0.0022	uM
2-(4-fluorophenyl)-6-methoxy-1,3-benzothiazole	347533: Displacement of [125I]IMPY from beta-amyloid plaques in Alzheimer’s disease patient brain homogenate	ki	0.0022	uM
4-(5-methoxy-1-benzofuran-2-yl)aniline	264125: Displacement of [125I]IMPY from beta amyloid in human corpse AD brain	ki	0.0023	uM
[1-[(2R,6S)-1-(4-chlorophenyl)sulfonyl-6-(3,5-difluorophenyl)piperidin-2-yl]cyclopropyl] 4-(2-hydroxyethyl)piperazine-1-carboxylate	301167: Inhibition of gamma-secretase assessed as reduction of membrane A-beta-40 level	ic50	0.0024	uM
N-[3-[(6R)-4-amino-2-cyano-6-methyl-7H-pyrazolo[1,5-a]pyrazin-6-yl]-4-fluorophenyl]-5-(difluoromethyl)pyrazine-2-carboxamide	1819117: Inhibition of human amyloid beta (1 to 42) in human SKNBE2 cells expressing wild-type amyloid precursor protein hAPP695 incubated for 18 hrs by sandwich ELISA	ic50	0.0025	uM
N-[3-[(6R)-4-amino-2-cyano-6-methyl-7H-pyrazolo[1,5-a]pyrazin-6-yl]-4-fluorophenyl]-5-fluoropyridine-2-carboxamide	1819117: Inhibition of human amyloid beta (1 to 42) in human SKNBE2 cells expressing wild-type amyloid precursor protein hAPP695 incubated for 18 hrs by sandwich ELISA	ic50	0.0026	uM
2-[4-(dimethylamino)phenyl]-1-benzofuran-5-ol	264125: Displacement of [125I]IMPY from beta amyloid in human corpse AD brain	ki	0.0028	uM
4-[2-(4-methoxyphenyl)ethynyl]phenol	286796: Displacement of [125I]IMPY from human beta amyloid plaque in brain homogenates	ki	0.0029	uM
4-[2-[4-[2-[2-(2-fluoroethoxy)ethoxy]ethoxy]phenyl]ethynyl]-N,N-dimethylaniline	286796: Displacement of [125I]IMPY from human beta amyloid plaque in brain homogenates	ki	0.0029	uM
Florbetapir F-18	445593: Binding affinity to Beta amyloid aggregates in Alzheimer’s disease patient brain by competitive binding assay	ki	0.0029	uM
4-(1-benzothiophen-2-yl)phenol	1500336: Inhibition of [125I]2-(3’-Iodo-4’-N-methylaminophenyl) benzothiazole binding to amyloid beta (1 to 40) (unknown origin) after 3 hrs by NaI well counting method	ki	0.0030	uM
[1-(4-phenoxyphenyl)triazol-4-yl]methyl 4-hydroxy-3-methoxybenzoate	2121957: Inhibition of amyloid beta (1 to 42) (unknown origin) aggregation incubated for 48 hrs by ThioflavinT staining based fluorescence assay	ic50	0.0030	uM
2-[2-[4-[2-[4-(methylamino)phenyl]ethynyl]phenoxy]ethoxy]ethanol	286796: Displacement of [125I]IMPY from human beta amyloid plaque in brain homogenates	ki	0.0031	uM
[4-[(2Z)-2-[9-[(E)-2-[4-(dimethylamino)phenyl]ethenyl]-2,3-dioxo-1,4,6,10-tetraoxa-5-boranuidaspiro[4.5]dec-8-en-7-ylidene]ethylidene]cyclohexa-2,5-dien-1-ylidene]-dimethylazanium	1884916: Binding affinity to human amyloid beta (1 to 42) monomer measured by fluorescence assay	kd	0.0032	uM

CTD chemical–gene interactions

303 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Copper	decreases reaction, increases chemical synthesis, increases abundance, affects binding, decreases expression (+13 more)	26
Zinc	decreases reaction, increases secretion, affects folding, increases reduction, increases reaction (+2 more)	10
sulindac sulfide	decreases activity, affects cleavage, affects reaction, increases reaction, affects localization	9
Hydrogen Peroxide	decreases reaction, decreases secretion, increases chemical synthesis, affects binding, affects expression (+4 more)	8
Lead	affects splicing, affects binding, affects cotreatment, affects expression, increases secretion (+4 more)	8
Resveratrol	decreases reaction, affects cotreatment, affects reaction, affects folding, affects binding (+6 more)	6
sodium arsenite	affects localization, affects cotreatment, increases expression, affects secretion, increases cleavage	4
Curcumin	decreases reaction, increases expression, affects binding, affects reaction	4
Ibuprofen	increases secretion, decreases expression, affects cleavage, affects cotreatment, decreases reaction (+1 more)	4
Tretinoin	increases metabolic processing, affects cotreatment, increases expression, increases reaction, decreases reaction (+2 more)	4
Trientine	increases activity, decreases expression, increases metabolic processing, affects binding, affects cotreatment (+3 more)	4
Particulate Matter	increases expression, decreases reaction, affects cotreatment, increases uptake, decreases expression (+4 more)	4
lead acetate	increases reaction, increases expression, decreases reaction, affects cotreatment, decreases expression (+2 more)	3
24-hydroxycholesterol	decreases secretion, increases metabolic processing, affects metabolic processing, increases activity, decreases metabolic processing	3
27-hydroxycholesterol	decreases metabolic processing, decreases secretion, increases expression	3
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	decreases expression, decreases reaction, affects localization, increases expression, increases phosphorylation (+3 more)	3
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	affects binding, decreases reaction, increases degradation, increases expression, decreases phosphorylation	3
Acetylcysteine	decreases reaction, increases abundance, increases expression, affects localization, increases activity (+1 more)	3
Acrolein	increases oxidation, increases reaction, increases abundance, affects binding, affects cotreatment (+1 more)	3
Air Pollutants	increases expression, increases reaction, decreases reaction, affects cotreatment, increases oxidation (+1 more)	3
Aluminum	increases expression, affects binding	3
Arsenic	affects methylation, decreases expression, increases abundance, affects cotreatment, affects expression	3
Benzo(a)pyrene	increases expression, decreases methylation	3
Cannabidiol	affects cotreatment, decreases expression, increases expression, decreases reaction, decreases response to substance	3
DDT	increases cleavage, increases expression, decreases degradation, increases secretion, decreases reaction	3
Estradiol	increases activity, increases cleavage, increases expression, increases secretion, decreases expression (+1 more)	3
Indomethacin	increases metabolic processing, increases secretion, affects cleavage, decreases reaction, increases expression (+1 more)	3
Paraquat	increases reaction, increases expression, increases response to substance, affects binding, decreases reaction	3
Penicillamine	affects binding, affects cotreatment, decreases reaction, increases chemical synthesis, increases oxidation (+2 more)	3
Quercetin	decreases phosphorylation, decreases reaction, increases abundance, increases activity, increases cleavage (+2 more)	3

ChEMBL screening assays

1744 unique, capped per target: 1699 binding, 44 functional, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1002439	Binding	Displacement of [125I]IMPY from beta-amyloid plaques in brain homogenate of patient with Alzheimer’s disease by gamma counting	11C-labelled PIB analogues as potential tracer agents for in vivo imaging of amyloid beta in Alzheimer’s disease. — *Eur J Med Chem*
CHEMBL1613905	Functional	PUBCHEM_BIOASSAY: Assay for Inhibitors of the fibrillation of the Beta-Amyloid Protein Fragment, A-beta 1-42. (Class of assay: confirmatory) [Related pubchem assays: 1460, 1468 ]	PubChem BioAssay data set
CHEMBL4826780	ADMET	Inhibition of amyloid beta(25 to 35) (unknown origin) binding to human SH-SY5Y cell plasma membrane at 10 uM measured after 20 mins by UV-vis microplate reader assay	Synthesis, biological evaluation and molecular modeling of benzofuran piperidine derivatives as Aβ antiaggregant. — *Eur J Med Chem*

Cellosaurus cell lines

87 cell lines: 54 induced pluripotent stem cell, 18 cancer cell line, 11 transformed cell line, 3 spontaneously immortalized cell line, 1 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_0523	SH-SY5Y-SPA4CT	Cancer cell line	Female
CVCL_2707	REM 885	Transformed cell line	Male
CVCL_A3ZL	ZZUi024-A	Induced pluripotent stem cell	Female
CVCL_A5CZ	HEK293 APPswe	Transformed cell line	Female
CVCL_A8YX	F15553	Induced pluripotent stem cell
CVCL_A8YY	F16574	Induced pluripotent stem cell	Sex unspecified
CVCL_A8YZ	UOMELBi002-A	Induced pluripotent stem cell	Sex unspecified
CVCL_A9QA	UEFi003-A	Induced pluripotent stem cell	Male
CVCL_B2RV	Abcam HEK293T APP KO	Transformed cell line	Female
CVCL_B5GR	XWHNi001-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 322 trials:

NCT	Phase	Status	Title
NCT04520308	Phase 4	UNKNOWN	An Open-label, Single-arm Longitudinal Study With Dupilumab for Patients With Atopic Dermatitis
NCT00009191	Phase 4	COMPLETED	The Depression in Alzheimer’s Disease Study (DIADS)
NCT00009217	Phase 4	COMPLETED	Treatment of Behavioral Symptoms in Alzheimer’s Disease
NCT00018278	Phase 4	COMPLETED	Electrophysiologic Measures of Treatment Response in Alzheimer Disease
NCT00035204	Phase 4	COMPLETED	A Study of the Effects on Sleep, Attention, and Gastrointestinal Tolerance of Galantamine and Donepezil in Patients With Alzheimer’s Disease
NCT00042172	Phase 4	COMPLETED	Treatment for Early Memory Loss
NCT00046358	Phase 4	COMPLETED	The Effect of Short-Term Statins and NSAIDs on Levels of Beta-Amyloid, a Protein Associated With Alzheimer’s Disease
NCT00104442	Phase 4	COMPLETED	Study of the Effects of Current Drug Treatments on Levels of Certain Brain Chemicals in Alzheimer’s Disease
NCT00120874	Phase 4	COMPLETED	Memantine and Comprehensive, Individualized Management of Alzheimer’s Disease and Caregiver Training
NCT00142324	Phase 4	UNKNOWN	CALM-AD
NCT00165724	Phase 4	COMPLETED	Alzheimer’s Disease Long-term Follow-up Study (ALF Study)
NCT00165750	Phase 4	TERMINATED	Correlation Between Regional Brain Volume and Response to Donepezil Treatment in AD Patients
NCT00202124	Phase 4	COMPLETED	Double Blind Study of Trp01 in Patients With Alzheimer’s Disease
NCT00208819	Phase 4	COMPLETED	A Comparison of Two Standard Therapies in the Management of Dementia With Agitation
NCT00216515	Phase 4	COMPLETED	The Efficacy of Galantamine on the Attention and the Frontal Function of the Patients With Dementia of Alzheimer Type
NCT00230568	Phase 4	COMPLETED	EARTH 413: A Study of Aricept in Hispanic Patients With Mild to Moderate Alzheimer’s Disease (AD)
NCT00234637	Phase 4	COMPLETED	Rivastigmine Monotherapy and Combination Therapy With Memantine in Patients With Moderately Severe Alzheimer’s Disease Who Failed to Benefit From Previous Cholinesterase Inhibitor Treatment
NCT00245206	Phase 4	COMPLETED	Side Effects of Newer Antipsychotics in Older Adults
NCT00254033	Phase 4	COMPLETED	Apathy Associated With Alzheimer’s Disease
NCT00260624	Phase 4	COMPLETED	Escitalopram Treatment of Patients With Agitated Dementia
NCT00303277	Phase 4	COMPLETED	Do HMG CoA Reductase Inhibitors Affect Abeta Levels?
NCT00305903	Phase 4	COMPLETED	Safety and Tolerability of Rivastigmine With Add-on Memantine in Patients With Probable Alzheimer’s Disease
NCT00306124	Phase 4	UNKNOWN	Dopaminergic Enhancement of Learning and Memory in Healthy Adults and Patients With Dementia/Mild Cognitive Impairment
NCT00334906	Phase 4	COMPLETED	Study of Memantine in Assessment of Selected Measures of Volumetric Magnetic Resonance Imaging (MRI) and Cognition in Moderate AD (Alzheimer’s Disease)
NCT00369603	Phase 4	TERMINATED	Functional Brain Imaging of Medication Treatment Response in Mild Alzheimer’s Disease Patients
NCT00375557	Phase 4	WITHDRAWN	Safety and Efficacy of Divalproex and Quetiapine in Elderly Alzheimer’s Dementia Patients
NCT00381381	Phase 4	COMPLETED	The Clinical Response of Choline Acetyltransferase and Apolipoprotein Epsilon Gene Polymorphisms to Donepezil in Alzheimer’s Disease
NCT00385684	Phase 4	COMPLETED	Low-Dose Opiate Therapy for Discomfort in Dementia (L-DOT)
NCT00401167	Phase 4	COMPLETED	Memantine for Agitation and Aggression in Severe Alzheimer’s Disease
NCT00403520	Phase 4	COMPLETED	Hippocampus Study: Comparative Effect of Donepezil 10mg/d and Placebo on Clinical and Radiological Markers
NCT00417482	Phase 4	COMPLETED	Antipsychotic Discontinuation in Alzheimer’s Disease
NCT00443014	Phase 4	COMPLETED	The Dementia Study in Northern Norway
NCT00469456	Phase 4	COMPLETED	Effect of Memantine on Functional Communication in Patients With Alzheimer’s Disease
NCT00476008	Phase 4	COMPLETED	Delaying the Progression of Driving Impairment in Individuals With Mild Alzheimer’s Disease
NCT00477659	Phase 4	COMPLETED	Neural Correlates In Mild Alzheimer’s Disease
NCT00480870	Phase 4	COMPLETED	The Effect of Anticholinesterase Drugs on Sleep in Alzheimer’s Disease Patients
NCT00495820	Phase 4	COMPLETED	Methylphenidate for Apathy in Alzheimer’s Dementia: A Controlled Study
NCT00523666	Phase 4	UNKNOWN	Diffusion Tensor Weighted MRI in Alzheimer’s Disease Modifying Treatment Effects of Galantamine (Reminyl®)
NCT00549601	Phase 4	COMPLETED	Convenience, Tolerability, and Safety of Change in the Administration of Rivastigmine From Capsules to a Transdermal Patch in Patients With Mild to Moderate Alzheimer’s Disease
NCT00551161	Phase 4	COMPLETED	Magnetic Resonance Spectroscopy Study of Memantine in Alzheimer’s Disease
NCT00561392	Phase 4	COMPLETED	Clinical Effectiveness of 10 cm^2 Rivastigmine Patch in Patients With Alzheimer’s Disease
NCT00622713	Phase 4	COMPLETED	A 24 Week, Multicenter, Open, Evaluation of the Clinical Effectiveness of the Once-daily 10 cm^2 Rivastigmine Patch Formulation in Patients With Probable Alzheimer’s Disease (EXTRA)
NCT00626210	Phase 4	TERMINATED	Modafinil Treatment for Sleep/Wake Disturbances in Older Adults
NCT00626613	Phase 4	UNKNOWN	The Relationship Between Risperdal Treatment and Quality of Life in Patients With Alzheimer’s Disease and Behavioural and Psychological Symptoms of Dementia (BPSD)
NCT00649220	Phase 4	TERMINATED	Memantine and Antipsychotics Use
NCT00706186	Phase 4	TERMINATED	Safety and Feasibility of Sodium Oxybate in Mild Alzheimer’s Disease Patients
NCT00711204	Phase 4	WITHDRAWN	Evaluating The Impact Of Donepezil Hydrochloride (Aricept) On Behavioral And Psychological Symptoms In Patients With Severe Alzheimer’s Disease
NCT00731224	Phase 4	COMPLETED	Compliance and Tolerability of Rivastigmine Transdermal Patch 10 cm² in Patients With Probable Alzheimer’s Disease.
NCT00792662	Phase 4	WITHDRAWN	Improving Function, Quality of Life, Glycemia in Diabetics With Dementia
NCT00800709	Phase 4	COMPLETED	Memantine and Changes of Biological Markers and Brain PET Imaging in Alzheimer’s Disease
NCT00862940	Phase 4	COMPLETED	A Clinical Study Evaluating the Effects of Memantine on Brain Atrophy in Patients With Alzheimer’s Disease
NCT00933608	Phase 4	COMPLETED	Effects of Memantine on Magnetic Resonance (MR) Spectroscopy in Subjects at Risk for Alzheimer’s Disease
NCT00948766	Phase 4	COMPLETED	Effects of Rivastigmine Patch on Activities of Daily Living and Cognition in Patients With Severe Dementia of the Alzheimer’s Type (ACTION) (Study Protocol CENA713DUS44, NCT00948766) and a 24 Week Open-label Extension to Study CENA713DUS44
NCT00950430	Phase 4	ENROLLING_BY_INVITATION	Imaging of Brain Amyloid Plaques in the Aging Population
NCT00980785	Phase 4	COMPLETED	Studying the Effects of Antihypertensives on Individuals at Risk for Alzheimer’s
NCT01025466	Phase 4	COMPLETED	Exelon Patch and Combination With Memantine Comparative Trial
NCT01047579	Phase 4	COMPLETED	A 12 Week, Multicenter, Open Label Evaluation of Caregiver Preference, Safety and Tolerability of Exelon® Patch (Rivastigmine Transdermal) in Patients With Alzheimer’s Disease
NCT01054976	Phase 4	COMPLETED	The Efficacy of Galantamine Treatment on Attention in Patients With Alzheimer’s Disease
NCT01119638	Phase 4	COMPLETED	Escitalopram Treatment for BPSD in Alzheimer’s Disease in Comparison to Risperidone
NCT01122329	Phase 4	COMPLETED	A Positron Emission Tomography (PET) Study Evaluating Brain Metabolism of a Medical Food in Alzheimer’s Disease

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for APP across ~30M SureChEMBL compounds — explore on Sugi Predict.