Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKFD7R4)

• DOT Name: Amyloid-beta precursor protein (APP)
• Synonyms: APP; 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; CVAP; PreA4; Protease nexin-II; PN-II
• Gene Name: APP
• Related Disease:
  Alzheimer disease type 1
  Cerebral amyloid angiopathy, APP-related
  ABeta amyloidosis, Arctic type
  ABeta amyloidosis, dutch type
  ABeta amyloidosis, Iowa type
  ABeta amyloidosis, Italian type
  ABetaA21G amyloidosis
  ABetaL34V amyloidosis
  Early-onset autosomal dominant Alzheimer disease
• UniProt ID: A4_HUMAN
• PDB ID: 1AAP ; 1AMB ; 1AMC ; 1AML ; 1BA4 ; 1BA6 ; 1BJB ; 1BJC ; 1BRC ; 1CA0 ; 1HZ3 ; 1IYT ; 1MWP ; 1OWT ; 1QCM ; 1QWP ; 1QXC ; 1QYT ; 1TAW ; 1TKN ; 1X11 ; 1Z0Q ; 1ZE7 ; 1ZE9 ; 1ZJD ; 2BEG ; 2BP4 ; 2FJZ ; 2FK1 ; 2FK2 ; 2FK3 ; 2FKL ; 2FMA ; 2G47 ; 2IPU ; 2LFM ; 2LLM ; 2LMN ; 2LMO ; 2LMP ; 2LMQ ; 2LNQ ; 2LOH ; 2LP1 ; 2LZ3 ; 2LZ4 ; 2M4J ; 2M9R ; 2M9S ; 2MGT ; 2MJ1 ; 2MPZ ; 2MVX ; 2MXU ; 2NAO ; 2OTK ; 2R0W ; 2WK3 ; 2Y29 ; 2Y2A ; 2Y3J ; 2Y3K ; 2Y3L ; 3AYU ; 3BAE ; 3BKJ ; 3DXC ; 3DXD ; 3DXE ; 3GCI ; 3IFL ; 3IFN ; 3IFO ; 3IFP ; 3JQ5 ; 3JQL ; 3JTI ; 3KTM ; 3L33 ; 3L81 ; 3MOQ ; 3MXC ; 3MXY ; 3NYJ ; 3NYL ; 3OVJ ; 3OW9 ; 3PZZ ; 3Q2X ; 3SV1 ; 3U0T ; 3UMH ; 3UMI ; 3UMK ; 4HIX ; 4JFN ; 4M1C ; 4MDR ; 4MVI ; 4MVK ; 4MVL ; 4NGE ; 4OJF ; 4ONF ; 4ONG ; 4PQD ; 4PWQ ; 4XXD ; 5AEF ; 5AM8 ; 5AMB ; 5BUO ; 5C67 ; 5CSZ ; 5HOW ; 5HOX ; 5HOY ; 5KK3 ; 5LFY ; 5LV0 ; 5MY4 ; 5MYO ; 5MYX ; 5ONP ; 5ONQ ; 5OQV ; 5TXD ; 5VOS ; 5VZY ; 5W3P ; 6CO3 ; 6GFI ; 6ITU ; 6IYC ; 6NB9 ; 6O4J ; 6OC9 ; 6OIZ ; 6RHY ; 6SHS ; 6SZF ; 6TI5 ; 6TI6 ; 6TI7 ; 6W0O ; 6WXM ; 6XOV ; 6YHF ; 6YHI ; 6YHO ; 6YHP ; 6YHX ; 7B3J ; 7B3K ; 7E6P ; 7F29 ; 7JXN ; 7JXO ; 7O1Q ; 7OW1 ; 7OXN ; 7Q4B ; 7Q4M ; 7RTZ ; 7U4P ; 7WFY ; 7WVY ; 7Y3J ; 7Y8Q ; 8AZS ; 8AZT ; 8B9Q ; 8B9R ; 8BFA ; 8BFB ; 8BFZ ; 8BG0 ; 8C3H ; 8EZD ; 8EZE ; 8FF2 ; 8FF3 ; 8OL2 ; 8OL3 ; 8OL5 ; 8OL6 ; 8OL7 ; 8OLG ; 8OLN ; 8OLO ; 8OLQ
• Pfam ID: PF10515 ; PF12924 ; PF12925 ; PF02177 ; PF03494 ; PF00014
• Sequence:
  MLPGLALLLLAAWTARALEVPTDGNAGLLAEPQIAMFCGRLNMHMNVQNGKWDSDPSGTK
  TCIDTKEGILQYCQEVYPELQITNVVEANQPVTIQNWCKRGRKQCKTHPHFVIPYRCLVG
  EFVSDALLVPDKCKFLHQERMDVCETHLHWHTVAKETCSEKSTNLHDYGMLLPCGIDKFR
  GVEFVCCPLAEESDNVDSADAEEDDSDVWWGGADTDYADGSEDKVVEVAEEEEVAEVEEE
  EADDDEDDEDGDEVEEEAEEPYEEATERTTSIATTTTTTTESVEEVVREVCSEQAETGPC
  RAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVCGSAMSQSLLKTTQEPLARD
  PVKLPTTAASTPDAVDKYLETPGDENEHAHFQKAKERLEAKHRERMSQVMREWEEAERQA
  KNLPKADKKAVIQHFQEKVESLEQEAANERQQLVETHMARVEAMLNDRRRLALENYITAL
  QAVPPRPRHVFNMLKKYVRAEQKDRQHTLKHFEHVRMVDPKKAAQIRSQVMTHLRVIYER
  MNQSLSLLYNVPAVAEEIQDEVDELLQKEQNYSDDVLANMISEPRISYGNDALMPSLTET
  KTTVELLPVNGEFSLDDLQPWHSFGADSVPANTENEVEPVDARPAADRGLTTRPGSGLTN
  IKTEEISEVKMDAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITL
  VMLKKKQYTSIHHGVVEVDAAVTPEERHLSKMQQNGYENPTYKFFEQMQN
• 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 protein 42 is a more effective reductant than amyloid-beta protein 40. 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. APP42-beta may activate mononuclear phagocytes in the brain and elicit inflammatory responses. 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.; 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.; N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6).
• 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.
• KEGG Pathway:
  Serotonergic sy.pse (hsa04726)
  Alzheimer disease (hsa05010)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• Reactome Pathway:
  ECM proteoglycans (R-HSA-3000178)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  G alpha (q) signalling events (R-HSA-416476)
  G alpha (i) signalling events (R-HSA-418594)
  Lysosome Vesicle Biogenesis (R-HSA-432720)
  Formyl peptide receptors bind formyl peptides and many other ligands (R-HSA-444473)
  TAK1-dependent IKK and NF-kappa-B activation (R-HSA-445989)
  The NLRP3 inflammasome (R-HSA-844456)
  Advanced glycosylation endproduct receptor signaling (R-HSA-879415)
  Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models (R-HSA-8862803)
  Post-translational protein phosphorylation (R-HSA-8957275)
  TRAF6 mediated NF-kB activation (R-HSA-933542)
  Insertion of tail-anchored proteins into the endoplasmic reticulum membrane (R-HSA-9609523)
  Purinergic signaling in leishmaniasis infection (R-HSA-9660826)
  Amyloid fiber formation (R-HSA-977225)
  Platelet degranulation (R-HSA-114608)
• BioCyc Pathway: MetaCyc:ENSG00000142192-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease type 1	DIS1ILLO	Strong	Autosomal dominant	[1]
Cerebral amyloid angiopathy, APP-related	DISM53WI	Strong	Autosomal dominant	[1]
ABeta amyloidosis, Arctic type	DISUMT1J	Supportive	Autosomal dominant	[2]
ABeta amyloidosis, dutch type	DIS6LNS5	Supportive	Autosomal dominant	[3]
ABeta amyloidosis, Iowa type	DIS8QSDB	Supportive	Autosomal dominant	[4]
ABeta amyloidosis, Italian type	DISUZKA2	Supportive	Autosomal dominant	[5]
ABetaA21G amyloidosis	DISHQ9MD	Supportive	Autosomal dominant	[6]
ABetaL34V amyloidosis	DISYU5HK	Supportive	Autosomal dominant	[7]
Early-onset autosomal dominant Alzheimer disease	DISFAUJO	Supportive	Autosomal dominant	[8]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Vitamin C	DMXJ7O8	Approved	Amyloid-beta precursor protein (APP) increases the oxidation of Vitamin C.	[65]

This DOT Affected the Regulation of Drug Effects of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Dinoprostone	DMTYOPD	Approved	Amyloid-beta precursor protein (APP) increases the secretion of Dinoprostone.	[66]
Arachidonic acid	DMUOQZD	Investigative	Amyloid-beta precursor protein (APP) increases the secretion of Arachidonic acid.	[66]
PGD2	DMYDW6J	Investigative	Amyloid-beta precursor protein (APP) increases the secretion of PGD2.	[66]
5S-HETE	DM3Z6G4	Investigative	Amyloid-beta precursor protein (APP) increases the secretion of 5S-HETE.	[66]
7,8-dihydrobiopterin	DMQU4XM	Investigative	Amyloid-beta precursor protein (APP) increases the abundance of 7,8-dihydrobiopterin.	[69]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Serotonin	DMOFCRY	Investigative	Amyloid-beta precursor protein (APP) increases the response to substance of Serotonin.	[67]
Heme	DMGC287	Investigative	Amyloid-beta precursor protein (APP) affects the binding of Heme.	[68]

45 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Amyloid-beta precursor protein (APP).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Amyloid-beta precursor protein (APP).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Amyloid-beta precursor protein (APP).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Amyloid-beta precursor protein (APP).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Amyloid-beta precursor protein (APP).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Amyloid-beta precursor protein (APP).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Amyloid-beta precursor protein (APP).	[15]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Amyloid-beta precursor protein (APP).	[16]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Amyloid-beta precursor protein (APP).	[17]
Marinol	DM70IK5	Approved	Marinol increases the expression of Amyloid-beta precursor protein (APP).	[18]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Amyloid-beta precursor protein (APP).	[19]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Amyloid-beta precursor protein (APP).	[20]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Amyloid-beta precursor protein (APP).	[21]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Amyloid-beta precursor protein (APP).	[22]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Amyloid-beta precursor protein (APP).	[23]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Amyloid-beta precursor protein (APP).	[24]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Amyloid-beta precursor protein (APP).	[26]
Mitomycin	DMH0ZJE	Approved	Mitomycin increases the expression of Amyloid-beta precursor protein (APP).	[27]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Amyloid-beta precursor protein (APP).	[28]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the activity of Amyloid-beta precursor protein (APP).	[29]
Ibuprofen	DM8VCBE	Approved	Ibuprofen decreases the expression of Amyloid-beta precursor protein (APP).	[30]
Methamphetamine	DMPM4SK	Approved	Methamphetamine increases the expression of Amyloid-beta precursor protein (APP).	[31]
Pioglitazone	DMKJ485	Approved	Pioglitazone decreases the expression of Amyloid-beta precursor protein (APP).	[30]
Liothyronine	DM6IR3P	Approved	Liothyronine decreases the expression of Amyloid-beta precursor protein (APP).	[32]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of Amyloid-beta precursor protein (APP).	[33]
Isoniazid	DM5JVS3	Approved	Isoniazid increases the expression of Amyloid-beta precursor protein (APP).	[10]
Sevoflurane	DMC9O43	Approved	Sevoflurane increases the expression of Amyloid-beta precursor protein (APP).	[36]
Heroin diacetylmorphine	DMDBWHY	Approved	Heroin diacetylmorphine decreases the expression of Amyloid-beta precursor protein (APP).	[38]
Ketamine	DMT5HA4	Approved	Ketamine increases the expression of Amyloid-beta precursor protein (APP).	[40]
Aluminium	DM6ECN9	Approved	Aluminium increases the expression of Amyloid-beta precursor protein (APP).	[41]
Trientine	DMD2WPG	Approved	Trientine decreases the expression of Amyloid-beta precursor protein (APP).	[42]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Amyloid-beta precursor protein (APP).	[43]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Amyloid-beta precursor protein (APP).	[44]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Amyloid-beta precursor protein (APP).	[19]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Amyloid-beta precursor protein (APP).	[50]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Amyloid-beta precursor protein (APP).	[51]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Amyloid-beta precursor protein (APP).	[10]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Amyloid-beta precursor protein (APP).	[52]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Amyloid-beta precursor protein (APP).	[53]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid affects the expression of Amyloid-beta precursor protein (APP).	[54]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Amyloid-beta precursor protein (APP).	[55]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Amyloid-beta precursor protein (APP).	[16]
Manganese	DMKT129	Investigative	Manganese increases the expression of Amyloid-beta precursor protein (APP).	[56]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug decreases the expression of Amyloid-beta precursor protein (APP).	[57]
Lead acetate	DML0GZ2	Investigative	Lead acetate increases the expression of Amyloid-beta precursor protein (APP).	[59]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Amyloid-beta precursor protein (APP).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Amyloid-beta precursor protein (APP).	[47]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Amyloid-beta precursor protein (APP).	[49]

21 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Indomethacin	DMSC4A7	Approved	Indomethacin affects the cleavage of Amyloid-beta precursor protein (APP).	[25]
Lovastatin	DM9OZWQ	Approved	Lovastatin increases the cleavage of Amyloid-beta precursor protein (APP).	[34]
Adenosine triphosphate	DM79F6G	Approved	Adenosine triphosphate increases the secretion of Amyloid-beta precursor protein (APP).	[35]
Flurbiprofen	DMGN4BY	Approved	Flurbiprofen decreases the secretion of Amyloid-beta precursor protein (APP).	[39]
Ademetionine	DMYQDBO	Approved	Ademetionine increases the secretion of Amyloid-beta precursor protein (APP).	[35]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate affects the folding of Amyloid-beta precursor protein (APP).	[45]
Coprexa	DMA0WEK	Phase 3	Coprexa affects the binding of Amyloid-beta precursor protein (APP).	[46]
Creatine ALS-08	DMKD2BQ	Phase 3	Creatine ALS-08 increases the secretion of Amyloid-beta precursor protein (APP).	[35]
(-)-Phenserine	DMNCY1I	Phase 3	(-)-Phenserine affects the binding of Amyloid-beta precursor protein (APP).	[46]
CHF-5074	DMTE071	Phase 2	CHF-5074 decreases the secretion of Amyloid-beta precursor protein (APP).	[39]
GM6001	DM7V9CT	Discontinued in Phase 2	GM6001 decreases the secretion of Amyloid-beta precursor protein (APP).	[48]
acrolein	DMAMCSR	Investigative	acrolein affects the binding of Amyloid-beta precursor protein (APP).	[58]
27-hydroxycholesterol	DM2L6OZ	Investigative	27-hydroxycholesterol decreases the secretion of Amyloid-beta precursor protein (APP).	[60]
Piceatannol	DMYOP45	Investigative	Piceatannol decreases the secretion of Amyloid-beta precursor protein (APP).	[61]
DEMETHOXYCURCUMIN	DMO5UGV	Investigative	DEMETHOXYCURCUMIN decreases the secretion of Amyloid-beta precursor protein (APP).	[62]
TRISMETHOXYRESVERATROL	DM6USPC	Investigative	TRISMETHOXYRESVERATROL decreases the secretion of Amyloid-beta precursor protein (APP).	[61]
Phorbol 12,13-butyrate	DMZWTY7	Investigative	Phorbol 12,13-butyrate increases the secretion of Amyloid-beta precursor protein (APP).	[64]
Guanosine-5'-Triphosphate	DMV2OJX	Investigative	Guanosine-5'-Triphosphate increases the secretion of Amyloid-beta precursor protein (APP).	[35]
Acetyl Coa	DMH65Q8	Investigative	Acetyl Coa increases the secretion of Amyloid-beta precursor protein (APP).	[35]
Phosphoenolpyruvate	DM2D947	Investigative	Phosphoenolpyruvate increases the secretion of Amyloid-beta precursor protein (APP).	[35]
CTP	DM4T62U	Investigative	CTP increases the secretion of Amyloid-beta precursor protein (APP).	[35]

2 Drug(s) Affected the Biochemical Pathways of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Penicillamine	DM40EF6	Approved	Penicillamine increases the metabolism of Amyloid-beta precursor protein (APP).	[37]
24(S)-hydroxycholesterol	DMGMWA6	Investigative	24(S)-hydroxycholesterol increases the metabolism of Amyloid-beta precursor protein (APP).	[63]

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