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): 637 total — 23 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 55
• Druggable target: yes — 40 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity little evidence
• Transcription factor: yes — 31 downstream targets (CollecTRI)
• MANE Select transcript: NM_000484

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: 40 — 30 protein_coding, 8 protein_coding_CDS_not_defined, 2 retained_intron

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

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.

FANTOM5 promoters (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

295 total, 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

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

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

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)

137 targeting APP, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

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

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)

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): P05067, A0A0A0MRG2, A0A140VJC8, E9PG40, 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 (230 total): mutagenesis site 41, strand 30, sequence variant 21, helix 16, binding site 15, site 15, chain 13, splice variant 13, modified residue 11, glycosylation site 10, region of interest 9, disulfide bond 9, turn 6, 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)

256 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
2FMA	X-RAY DIFFRACTION	0.85
6NB9	ELECTRON CRYSTALLOGRAPHY	1.05
6OIZ	ELECTRON CRYSTALLOGRAPHY	1.1
8T82	X-RAY DIFFRACTION	1.1
5ONQ	X-RAY DIFFRACTION	1.17
3JQL	X-RAY DIFFRACTION	1.2
3PZZ	X-RAY DIFFRACTION	1.29
4PQD	X-RAY DIFFRACTION	1.33
5ONP	X-RAY DIFFRACTION	1.34
5ONR	X-RAY DIFFRACTION	1.39
4PWQ	X-RAY DIFFRACTION	1.4
7OW1	X-RAY DIFFRACTION	1.4
6O4J	ELECTRON CRYSTALLOGRAPHY	1.4
5VOS	ELECTRON CRYSTALLOGRAPHY	1.42
3Q2X	X-RAY DIFFRACTION	1.45
5TXD	X-RAY DIFFRACTION	1.45
5MYX	X-RAY DIFFRACTION	1.49
1AAP	X-RAY DIFFRACTION	1.5
3IFL	X-RAY DIFFRACTION	1.5
3IFN	X-RAY DIFFRACTION	1.5
4MVK	X-RAY DIFFRACTION	1.5
8T89	X-RAY DIFFRACTION	1.5
5AMB	X-RAY DIFFRACTION	1.55
3BKJ	X-RAY DIFFRACTION	1.59
5MYO	X-RAY DIFFRACTION	1.59
3BAE	X-RAY DIFFRACTION	1.59
2FK1	X-RAY DIFFRACTION	1.6
3L81	X-RAY DIFFRACTION	1.6
2FJZ	X-RAY DIFFRACTION	1.61
2FK2	X-RAY DIFFRACTION	1.65

Predicted structure (AlphaFold)

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

Antibody-complex structures (SAbDab): 28 — 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 (+3 more)

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): 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) …

Ligand- & substrate-binding residues (15): 96–110; 147; 151; 168; 183; 186; 187; 677; 677; 681; 681; 684 …

Post-translational modifications (12): 198, 206, 217, 262, 336, 441, 497, 729, 730, 743, 757, 763

Disulfide bonds (9): 38–62, 73–117, 98–105, 133–187, 144–174, 158–186, 291–341, 300–324, 316–337

Glycosylation sites (10): 542, 571, 633, 651, 652, 656, 659, 663, 667, 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

69 pathways

ID	Pathway
R-HSA-114608	Platelet degranulation
R-HSA-3000178	ECM proteoglycans
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-416476	G alpha (q) signalling events
R-HSA-418594	G alpha (i) signalling events
R-HSA-432720	Lysosome Vesicle Biogenesis
R-HSA-444473	Formyl peptide receptors bind formyl peptides and many other ligands
R-HSA-445989	TAK1-dependent IKK and NF-kappa-B activation
R-HSA-844456	The NLRP3 inflammasome
R-HSA-879415	Advanced glycosylation endproduct receptor signaling
R-HSA-8862803	Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models
R-HSA-8957275	Post-translational protein phosphorylation
R-HSA-933542	TRAF6 mediated NF-kB activation
R-HSA-9609523	Insertion of tail-anchored proteins into the endoplasmic reticulum membrane
R-HSA-9660826	Purinergic signaling in leishmaniasis infection
R-HSA-9769739	Regulation of clotting cascade
R-HSA-977225	Amyloid fiber formation
R-HSA-9936686	Aggregated β-amyloid interacts with fibrinogen
R-HSA-9936900	Aggregated β-amyloid induces FXII autocatalysis
R-HSA-9837999	Mitochondrial protein degradation
R-HSA-109582	Hemostasis
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1474244	Extracellular matrix organization
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-166016	Toll Like Receptor 4 (TLR4) Cascade
R-HSA-166058	MyD88:MAL(TIRAP) cascade initiated on plasma membrane
R-HSA-166166	MyD88-independent TLR4 cascade
R-HSA-168138	Toll Like Receptor 9 (TLR9) Cascade
R-HSA-168142	Toll Like Receptor 10 (TLR10) 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 (75): 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 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)

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 (44): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), 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), 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)

Reactome top-level categories

Rollup of top-22 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

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
vesicle-mediated transport	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
cognition	1
learning or memory	1
reproductive behavior	1
transport along microtubule	1

Protein interactions and networks

STRING

7062 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
APP	APOE	P02649	999
APP	BACE1	P56817	999
APP	APBB1	O00213	998
APP	SORL1	Q92673	994
APP	TNFRSF21	O75509	993
APP	PSEN1	P49768	992
APP	APBA2	Q99767	988
APP	MAPT	P10636	986
APP	NAE1	Q13564	986
APP	CD74	P04233	985
APP	PRNP	P04156	984
APP	SPON1	Q9HCB6	980
APP	KAT5	Q92993	973
APP	APBB2	Q92870	966
APP	CLU	P10909	964

IntAct

1656 interactions, top by confidence:

A	B	Type	Score
APP	APP	psi-mi:“MI:0915”(physical association)	0.990
BACE1	APP	psi-mi:“MI:0570”(protein cleavage)	0.870
BACE1	APP	psi-mi:“MI:0403”(colocalization)	0.870
APP	BACE1	psi-mi:“MI:0915”(physical association)	0.870
BACE1	APP	psi-mi:“MI:2364”(proximity)	0.870
ITM2B	APP	psi-mi:“MI:0915”(physical association)	0.770
APP	MAPT	psi-mi:“MI:0217”(phosphorylation reaction)	0.750
APP	MAPT	psi-mi:“MI:0407”(direct interaction)	0.750
MAPT	APP	psi-mi:“MI:0407”(direct interaction)	0.750
MAPT	APP	psi-mi:“MI:0403”(colocalization)	0.750
APP	CALR	psi-mi:“MI:0914”(association)	0.740
APP	PDIA3	psi-mi:“MI:0915”(physical association)	0.700
PDIA3	APP	psi-mi:“MI:0915”(physical association)	0.700
SORL1	APP	psi-mi:“MI:0915”(physical association)	0.690
SORL1	APP	psi-mi:“MI:0403”(colocalization)	0.690
APBA2	APP	psi-mi:“MI:0407”(direct interaction)	0.690
PSEN2	APP	psi-mi:“MI:0915”(physical association)	0.680
APP	STXBP1	psi-mi:“MI:0915”(physical association)	0.670
APP	ADAM10	psi-mi:“MI:2364”(proximity)	0.660
ADAM10	APP	psi-mi:“MI:2364”(proximity)	0.660
ADAM10	APP	psi-mi:“MI:0915”(physical association)	0.660
APP	PIN1	psi-mi:“MI:0403”(colocalization)	0.650
PSEN1	APP	psi-mi:“MI:0915”(physical association)	0.630
APP	TNFRSF21	psi-mi:“MI:0407”(direct interaction)	0.620

BioGRID (2968): APP (Protein-peptide), SNX27 (Reconstituted Complex), APP (Affinity Capture-MS), MAPT (Reconstituted Complex), MAPT (Protein-peptide), QRICH1 (Two-hybrid), QRICH1 (Affinity Capture-Western), APP (Affinity Capture-Western), APP (Affinity Capture-MS), APP (Two-hybrid), APP (Biochemical Activity), APP (Affinity Capture-Western), APP (Biochemical Activity), APP (Affinity Capture-Western), GSAP (Affinity Capture-Western)

ESM2 similar proteins: A0A096LP55, A0A1D8PJT8, A1L243, A1L3N6, A6H767, A9ULB4, P00126, P00429, P05067, P07919, P08592, P12023, P13805, P14854, P23025, P27088, P28656, P36233, P36378, P48504, P55209, P56277, P79307, P99028, Q0P451, Q0VBY0, Q15545, Q28CA1, Q28EB4, Q2HJG8, Q4R374, Q4R5A5, Q4U0Y4, Q53CG4, Q5IS80, Q5M9I5, Q5R4D4, Q5R7L9, Q5RCT0, Q64267

Diamond homologs: A0A3G2FQK2, A0A6B7FA07, A0A6B7FBD3, A0A6B7FEJ3, A0A6P8HC43, A5X2X1, A8Y7N4, A8Y7N7, A8Y7N8, A8Y7N9, A8Y7P0, A8Y7P2, A8Y7P6, B1B5I8, B2G331, B5KL37, B6ZIW0, C0HJF3, C0HJF4, C0HJU6, C0HJU7, C0HK72, C0HK73, C0HK74, C0HLA7, C0HLB2, C0HMC7, C1IBY4, C8YJ94, C8YJ95, C8YJ96, C8YJ97, D8KY58, H2A0N9, H6VC05, O54819, P00990, P00991, P00994, P05067

SIGNOR signaling

56 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

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 133 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
Nuclear signaling by ERBB4	5	16.3×	2e-03
Vesicle-mediated transport	12	3.9×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
membrane protein ectodomain proteolysis	6	32.1×	2e-05
neuron apoptotic process	6	9.2×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	23
Likely pathogenic	8
Uncertain significance	272
Likely benign	188
Benign	70

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1353302	NC_000021.8:g.(?27251861)(27544138_?)dup	Pathogenic
1457308	NM_000484.4(APP):c.2145_2146delinsTG (p.Ile716Val)	Pathogenic
1526702	GRCh37/hg19 21q11.2-21.3(chr21:15006457-27430623)	Pathogenic
1807236	Single allele	Pathogenic
18087	NM_000484.4(APP):c.2077G>C (p.Glu693Gln)	Pathogenic
18088	NM_000484.4(APP):c.2149G>A (p.Val717Ile)	Pathogenic
18089	NM_000484.4(APP):c.2149G>T (p.Val717Phe)	Pathogenic
18090	NM_000484.4(APP):c.2150T>G (p.Val717Gly)	Pathogenic
18091	NM_000484.4(APP):c.2075C>G (p.Ala692Gly)	Pathogenic
18093	NM_000484.4(APP):c.2010_2011inv (p.Lys670_Met671delinsAsnLeu)	Pathogenic
18096	NM_000484.4(APP):c.2146A>G (p.Ile716Val)	Pathogenic
18098	NM_000484.4(APP):c.2078A>G (p.Glu693Gly)	Pathogenic
18099	NM_000484.4(APP):c.2077G>A (p.Glu693Lys)	Pathogenic
18100	NM_000484.4(APP):c.2141C>T (p.Thr714Ile)	Pathogenic
18101	NM_000484.4(APP):c.2080G>A (p.Asp694Asn)	Pathogenic
18102	NM_000484.4(APP):c.2140A>G (p.Thr714Ala)	Pathogenic
18105	NM_000484.4(APP):c.2149G>C (p.Val717Leu)	Pathogenic
18106	NM_000484.4(APP):c.2018C>T (p.Ala673Val)	Pathogenic
2423147	NC_000021.8:g.(?27113910)(27542938_?)dup	Pathogenic
2498894	NM_000484.4(APP):c.2146A>T (p.Ile716Phe)	Pathogenic
3338917	NC_000021.8:g.(?27252860)(27543089_?)dup	Pathogenic
98238	NM_000484.4(APP):c.2144T>C (p.Val715Ala)	Pathogenic
98240	NM_000484.4(APP):c.2147T>C (p.Ile716Thr)	Pathogenic
1298879	NM_000484.4(APP):c.2148C>G (p.Ile716Met)	Likely pathogenic
1342870	NM_000484.4(APP):c.2155A>C (p.Thr719Pro)	Likely pathogenic
18094	NM_000484.4(APP):c.2137G>A (p.Ala713Thr)	Likely pathogenic
18103	NM_000484.4(APP):c.2113C>G (p.Leu705Val)	Likely pathogenic
2628367	NM_000484.4(APP):c.2061A>C (p.Lys687Asn)	Likely pathogenic
3382968	NM_000484.4(APP):c.2059A>C (p.Lys687Gln)	Likely pathogenic
3690355	NM_000484.4(APP):c.2138C>A (p.Ala713Glu)	Likely pathogenic

SpliceAI

4341 predictions. Top by Δscore:

Variant	Effect	Δscore
21:25881767:TCAAC:T	acceptor_gain	1.0000
21:25881768:CAAC:C	acceptor_gain	1.0000
21:25881768:CAACC:C	acceptor_gain	1.0000
21:25881769:AAC:A	acceptor_gain	1.0000
21:25881769:AACCT:A	acceptor_loss	1.0000
21:25881770:AC:A	acceptor_gain	1.0000
21:25881770:ACCTG:A	acceptor_loss	1.0000
21:25881771:CC:C	acceptor_gain	1.0000
21:25881772:C:CC	acceptor_gain	1.0000
21:25881773:T:A	acceptor_loss	1.0000
21:25891720:A:AC	donor_gain	1.0000
21:25891720:ACCT:A	donor_gain	1.0000
21:25891721:C:CC	donor_gain	1.0000
21:25891721:CCT:C	donor_gain	1.0000
21:25891721:CCTC:C	donor_gain	1.0000
21:25891864:AACAC:A	acceptor_gain	1.0000
21:25891865:ACAC:A	acceptor_gain	1.0000
21:25891866:CAC:C	acceptor_gain	1.0000
21:25891866:CACCT:C	acceptor_gain	1.0000
21:25891867:AC:A	acceptor_gain	1.0000
21:25891868:CC:C	acceptor_gain	1.0000
21:25891869:C:CC	acceptor_gain	1.0000
21:25891869:C:T	acceptor_gain	1.0000
21:25891870:T:C	acceptor_gain	1.0000
21:25891870:T:TC	acceptor_gain	1.0000
21:25891877:C:CT	acceptor_gain	1.0000
21:25897569:GTACC:G	donor_loss	1.0000
21:25897571:A:AC	donor_gain	1.0000
21:25897571:A:AT	donor_loss	1.0000
21:25897571:AC:A	donor_gain	1.0000

AlphaMissense

5117 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:25881704:G:T	P760Q	1.000
21:25881706:A:C	N759K	1.000
21:25881706:A:T	N759K	1.000
21:25881728:A:G	M752T	1.000
21:25881737:A:G	L749P	1.000
21:25881743:C:G	R747P	1.000
21:25891783:A:T	V717D	1.000
21:25891795:G:T	A713E	1.000
21:25891798:A:C	I712R	1.000
21:25891798:A:T	I712K	1.000
21:25891801:A:T	V711D	1.000
21:25891807:C:T	G709D	1.000
21:25891808:C:G	G709R	1.000
21:25891810:C:T	G708D	1.000
21:25891811:C:G	G708R	1.000
21:25891816:A:C	M706R	1.000
21:25891816:A:T	M706K	1.000
21:25955672:A:C	H514Q	1.000
21:25955672:A:T	H514Q	1.000
21:25955673:T:G	H514P	1.000
21:25955674:G:C	H514D	1.000
21:25955683:G:C	H511D	1.000
21:25955716:C:G	A500P	1.000
21:25955733:A:G	L494P	1.000
21:25975157:G:C	H457Q	1.000
21:25975157:G:T	H457Q	1.000
21:25975159:G:C	H457D	1.000
21:25975170:A:G	L453P	1.000
21:25976014:C:A	W413C	1.000
21:25976014:C:G	W413C	1.000

dbSNP variants (sampled 300 via entrez): RS1000007183 (21:26125674 G>A,C), RS1000008568 (21:26071470 A>G,T), RS1000026467 (21:26157163 G>A,C), RS1000029474 (21:26166944 G>C), RS1000031783 (21:26079596 A>G), RS1000037661 (21:25960979 C>A), RS1000042245 (21:26144679 A>G), RS1000052017 (21:25984966 A>G), RS1000061681 (21:26000747 C>T), RS1000079556 (21:25914678 C>T), RS1000080144 (21:25880266 T>C), RS1000086194 (21:26120225 G>C), RS1000089493 (21:25916192 G>C), RS1000111460 (21:26162512 G>C), RS1000115922 (21:26099241 C>T)

Disease associations

OMIM: gene MIM:104760 | disease phenotypes: MIM:605714, MIM:104300, MIM:604364

GenCC curated gene-disease

Disease	Classification	Inheritance
Alzheimer disease type 1	Strong	Autosomal dominant
cerebral amyloid angiopathy, APP-related	Strong	Autosomal dominant
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 (1)

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

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

Mondo (14): Alzheimer disease (MONDO:0004975), cerebral amyloid angiopathy, APP-related (MONDO:0011583), Alzheimer disease type 1 (MONDO:0007088), 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), cerebral amyloid angiopathy (MONDO:0005620), primary ovarian failure (MONDO:0005387), familial focal epilepsy with variable foci (MONDO:0020310), vascular dementia (MONDO:0004648), early-onset autosomal dominant Alzheimer disease (MONDO:0015140), ABetaL34V amyloidosis (MONDO:0017945)

Orphanet (11): 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), Familial focal epilepsy with variable foci (Orphanet:98820), NON RARE IN EUROPE: Alzheimer disease (Orphanet:238616), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

55 total (30 of 55 shown, 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)

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST003082_7	Longitudinal change in brain amyloid plaque burden	3.000000e-06
GCST006279_3	Cerebrospinal fluid α-synuclein levels	2.000000e-07
GCST009306_3	Spatial processing	2.000000e-06
GCST011743_57	HDL cholesterol levels in HIV infection	8.000000e-06
GCST012182_4	Alzheimer’s disease	1.000000e-11
GCST90011768_17	Glaucoma (primary open-angle)	7.000000e-06
GCST90011770_82	Glaucoma (primary open-angle)	3.000000e-07

EFO canonical traits (4, from GWAS)

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 (6)

Descriptor	Name	Tree numbers
D000544	Alzheimer Disease	C10.228.140.380.100; C10.574.945.249; F03.615.400.100
D016657	Cerebral Amyloid Angiopathy	C10.228.140.300.510.200.200; C14.907.253.560.200.200; C18.452.845.500.100
D015140	Dementia, Vascular	C10.228.140.300.400; C10.228.140.300.510.800.500; C10.228.140.380.230; C10.228.140.695.500; C14.907.137.126.372.500; C14.907.253.560.350.500; F03.615.400.350
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750
C536594	Alzheimer disease type 1 (supp.)
C565785	Epilepsy, Partial, with Variable Foci (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2487 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

40 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,385,420 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1774461	FLORBETAPIR F 18	4	393
CHEMBL1908919	FLORBETAPIR	4	690
CHEMBL191083	METHYLENE BLUE CATION	4	7,622
CHEMBL2042122	FLUTEMETAMOL F 18	4	268
CHEMBL38	TRETINOIN	4	194,008
CHEMBL405110	METHYLENE BLUE ANHYDROUS	4	113,934
CHEMBL497	CLIOQUINOL	4	12,977
CHEMBL502	DONEPEZIL	4	43,493
CHEMBL566752	FLORBETABEN F18	4	763
CHEMBL573	NIACIN	4	351,963
CHEMBL579205	FLUTEMETAMOL	4	321
CHEMBL64894	GENTIAN VIOLET	4	111,449
CHEMBL682	AMODIAQUINE	4	7,153
CHEMBL723	CARVEDILOL	4	30,225
CHEMBL76	CHLOROQUINE	4	58,679
CHEMBL95	TACRINE	4	35,360
CHEMBL986	RETINOL	4	277,603
CHEMBL140	CURCUMIN	3	93,882
CHEMBL145	CAFFEIC ACID	3	36,305
CHEMBL149082	TRAMIPROSATE	3	8,332
CHEMBL165	RESVERATROL	3
CHEMBL2048308	FLUTAFURANOL	3
CHEMBL297453	EPIGALOCATECHIN GALLATE	3
CHEMBL3989948	LANABECESTAT	3
CHEMBL50	QUERCETIN	3
CHEMBL858	EDETIC ACID	3
CHEMBL1368322	PARAROSANILINE	2
CHEMBL151	LUTEOLIN	2
CHEMBL207456	PITTSBURGH COMPOUND B	2
CHEMBL2364601	AFTOBETIN	2

PharmGKB: 1 entry (VIP=true, CPIC=false)

Binding affinities (BindingDB)

404 measured of 420 human assays (420 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
US10231967, Example 122	IC50	0.1 nM	US-10231967: Compounds and their use as BACE inhibitors
US8865911, 114	IC50	0.14 nM	US-10231967: Compounds and their use as BACE inhibitors
US10231967, Example 94-Isomer-1	IC50	0.17 nM	US-10231967: Compounds and their use as BACE inhibitors
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
US8865911, 20t	IC50	0.36 nM	US-10231967: Compounds and their use as BACE inhibitors
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
(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
US8865911, 94 Isomer 2	IC50	0.56 nM	US-10231967: Compounds and their use as BACE inhibitors
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
US10231967, Example 20aa	IC50	0.72 nM	US-10231967: Compounds and their use as BACE inhibitors
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
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
US9000185, 8	IC50	0.8 nM	US-9000185: Cycloalkyl ether compounds and their use as BACE inhibitors
(R,E)-5-(2-(6-(1H-imidazol-1-yl)pyridin-3-yl)vinyl)-2-(2-(methoxymethyl)-4-(5-(methoxymethyl)pyrimidin-2-yl)piperazin-1-yl)pyrimidine	KI	0.8 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-5-(5-(2-(2-(3-((2-fluoroethoxy)methyl)-4-(1,3,5-triazin-2-yl)piperazin-1-yl)pyrimidin-5-yl)vinyl)pyridin-2-yl)oxazole	KI	0.8 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
US8865911, 68 Isomer 1	IC50	0.81 nM	US-10231967: Compounds and their use as BACE inhibitors
US8865911, 98	IC50	0.82 nM	US-10231967: Compounds and their use as BACE inhibitors
US8865911, 135	IC50	0.85 nM	US-10231967: Compounds and their use as BACE inhibitors
US9000185, 4, isomer 1	IC50	0.9 nM	US-9000185: Cycloalkyl ether compounds and their use as BACE inhibitors
(R,E)-5-(2-(6-(1H-imidazol-1-yl)pyridin-3-yl)vinyl)-2-(3-(methoxymethyl)-4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidine	KI	0.9 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-5-(2-(6-(1H-imidazol-1-yl)pyridin-3-yl)vinyl)-2-(4-(4-fluoropyridin-2-yl)-2-(methoxymethyl)piperazin-1-yl)pyrimidine	KI	0.9 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-(5-methylpyrimidin-2-yl)piperazin-1-yl)pyrimidine	KI	0.9 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-5-(2-(6-(1H-imidazol-1-yl)pyridin-3-yl)vinyl)-2-(4-(6-fluoropyridin-3-yl)-2-(methoxymethyl)piperazin-1-yl)pyrimidine	KI	0.9 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
3-(((R)-4-(5-((6-(1H-imidazol-1-yl)pyridin-3-yl)ethynyl)pyrimidin-2-yl)-1-(pyrimidin-2-yl)piperazin-2-yl)methoxy)-2-fluoropropan-1-ol	KI	0.913 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R)-7-(5-((2-(3-((2-fluoroethoxy)methyl)-4-(1,3,5-triazin-2-yl)piperazin-1-yl)pyrimidin-5-yl)ethynyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine	KI	0.915 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
US8865911, 87	IC50	0.93 nM	US-10231967: Compounds and their use as BACE inhibitors
(R,E)-5-(5-(2-(2-(3-((2-fluoroethoxy)methyl)-4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-5-yl)vinyl)pyridin-2-yl)oxazole	KI	0.94 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
US8865911, 84	IC50	0.99 nM	US-10231967: Compounds and their use as BACE inhibitors
N-[[(6aR,7R,10aS)-10a-(4-chlorophenyl)sulfonyl-1,4-difluoro-6,6a,7,8,9,10-hexahydrobenzo[c]chromen-7-yl]methyl]ethanesulfonamide	IC50	1 nM	US-8569521: Benzenesulfonyl-chromane, thiochromane, tetrahydronaphthalene and related gamma secretase inhibitors
US8865911, 73	IC50	1 nM	US-9000182: 2H-imidazol-4-amine compounds and their use as BACE inhibitors
US9000184, 6, isomer 1	IC50	1 nM	US-9000184: Cyclohexane-1,2′-naphthalene-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

753 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
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
2-[2-[2-[4-[2-[4-(dimethylamino)phenyl]ethynyl]phenoxy]ethoxy]ethoxy]ethanol	286796: Displacement of [125I]IMPY from human beta amyloid plaque in brain homogenates	ki	0.0034	uM

CTD chemical–gene interactions

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

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

84 cell lines: 54 induced pluripotent stem cell, 17 cancer cell line, 9 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)

320 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04520308	PHASE4	UNKNOWN	An Open-label, Single-arm Longitudinal Study With Dupilumab for Patients With Atopic Dermatitis
NCT00009191	PHASE4	COMPLETED	The Depression in Alzheimer’s Disease Study (DIADS)
NCT00009217	PHASE4	COMPLETED	Treatment of Behavioral Symptoms in Alzheimer’s Disease
NCT00018278	PHASE4	COMPLETED	Electrophysiologic Measures of Treatment Response in Alzheimer Disease
NCT00035204	PHASE4	COMPLETED	A Study of the Effects on Sleep, Attention, and Gastrointestinal Tolerance of Galantamine and Donepezil in Patients With Alzheimer’s Disease
NCT00042172	PHASE4	COMPLETED	Treatment for Early Memory Loss
NCT00046358	PHASE4	COMPLETED	The Effect of Short-Term Statins and NSAIDs on Levels of Beta-Amyloid, a Protein Associated With Alzheimer’s Disease
NCT00104442	PHASE4	COMPLETED	Study of the Effects of Current Drug Treatments on Levels of Certain Brain Chemicals in Alzheimer’s Disease
NCT00120874	PHASE4	COMPLETED	Memantine and Comprehensive, Individualized Management of Alzheimer’s Disease and Caregiver Training
NCT00142324	PHASE4	UNKNOWN	CALM-AD
NCT00165724	PHASE4	COMPLETED	Alzheimer’s Disease Long-term Follow-up Study (ALF Study)
NCT00165750	PHASE4	TERMINATED	Correlation Between Regional Brain Volume and Response to Donepezil Treatment in AD Patients
NCT00202124	PHASE4	COMPLETED	Double Blind Study of Trp01 in Patients With Alzheimer’s Disease
NCT00208819	PHASE4	COMPLETED	A Comparison of Two Standard Therapies in the Management of Dementia With Agitation
NCT00216515	PHASE4	COMPLETED	The Efficacy of Galantamine on the Attention and the Frontal Function of the Patients With Dementia of Alzheimer Type
NCT00230568	PHASE4	COMPLETED	EARTH 413: A Study of Aricept in Hispanic Patients With Mild to Moderate Alzheimer’s Disease (AD)
NCT00234637	PHASE4	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	PHASE4	COMPLETED	Side Effects of Newer Antipsychotics in Older Adults
NCT00254033	PHASE4	COMPLETED	Apathy Associated With Alzheimer’s Disease
NCT00260624	PHASE4	COMPLETED	Escitalopram Treatment of Patients With Agitated Dementia
NCT00303277	PHASE4	COMPLETED	Do HMG CoA Reductase Inhibitors Affect Abeta Levels?
NCT00305903	PHASE4	COMPLETED	Safety and Tolerability of Rivastigmine With Add-on Memantine in Patients With Probable Alzheimer’s Disease
NCT00306124	PHASE4	UNKNOWN	Dopaminergic Enhancement of Learning and Memory in Healthy Adults and Patients With Dementia/Mild Cognitive Impairment
NCT00334906	PHASE4	COMPLETED	Study of Memantine in Assessment of Selected Measures of Volumetric Magnetic Resonance Imaging (MRI) and Cognition in Moderate AD (Alzheimer’s Disease)
NCT00369603	PHASE4	TERMINATED	Functional Brain Imaging of Medication Treatment Response in Mild Alzheimer’s Disease Patients
NCT00375557	PHASE4	WITHDRAWN	Safety and Efficacy of Divalproex and Quetiapine in Elderly Alzheimer’s Dementia Patients
NCT00381381	PHASE4	COMPLETED	The Clinical Response of Choline Acetyltransferase and Apolipoprotein Epsilon Gene Polymorphisms to Donepezil in Alzheimer’s Disease
NCT00385684	PHASE4	COMPLETED	Low-Dose Opiate Therapy for Discomfort in Dementia (L-DOT)
NCT00401167	PHASE4	COMPLETED	Memantine for Agitation and Aggression in Severe Alzheimer’s Disease
NCT00403520	PHASE4	COMPLETED	Hippocampus Study: Comparative Effect of Donepezil 10mg/d and Placebo on Clinical and Radiological Markers
NCT00417482	PHASE4	COMPLETED	Antipsychotic Discontinuation in Alzheimer’s Disease
NCT00443014	PHASE4	COMPLETED	The Dementia Study in Northern Norway
NCT00469456	PHASE4	COMPLETED	Effect of Memantine on Functional Communication in Patients With Alzheimer’s Disease
NCT00476008	PHASE4	COMPLETED	Delaying the Progression of Driving Impairment in Individuals With Mild Alzheimer’s Disease
NCT00477659	PHASE4	COMPLETED	Neural Correlates In Mild Alzheimer’s Disease
NCT00480870	PHASE4	COMPLETED	The Effect of Anticholinesterase Drugs on Sleep in Alzheimer’s Disease Patients
NCT00495820	PHASE4	COMPLETED	Methylphenidate for Apathy in Alzheimer’s Dementia: A Controlled Study
NCT00523666	PHASE4	UNKNOWN	Diffusion Tensor Weighted MRI in Alzheimer’s Disease Modifying Treatment Effects of Galantamine (Reminyl®)
NCT00549601	PHASE4	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	PHASE4	COMPLETED	Magnetic Resonance Spectroscopy Study of Memantine in Alzheimer’s Disease