Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTG51ON)

• DTT Name: APP messenger RNA (APP mRNA)
• Synonyms: Vascular beta-amyloid (mRNA); Protease nexin-II (mRNA); PreA4 (mRNA); PN-II (mRNA); Cerebral vascular amyloidpeptide (mRNA); Cerebral vascular amyloid peptide (mRNA); CVAP (mRNA); Beta-amyloid peptide (mRNA); Amyloid-beta precursor protein (mRNA); Amyloid-beta A4 protein (mRNA); Amyloid precursor protein (mRNA); Amyloid beta precursor protein (mRNA); Alzheimer's disease amyloid protein (mRNA); Alzheimer disease amyloid protein (mRNA); APPI (mRNA); AD1 (mRNA); ABPP (mRNA); A4 (mRNA)
• Gene Name: APP
• DTT Type: Literature-reported target; [1]
• BioChemical Class: mRNA target
• UniProt ID: A4_HUMAN
• TTD ID: T23359
• Sequence:
  MLPGLALLLLAAWTARALEVPTDGNAGLLAEPQIAMFCGRLNMHMNVQNGKWDSDPSGTK
  TCIDTKEGILQYCQEVYPELQITNVVEANQPVTIQNWCKRGRKQCKTHPHFVIPYRCLVG
  EFVSDALLVPDKCKFLHQERMDVCETHLHWHTVAKETCSEKSTNLHDYGMLLPCGIDKFR
  GVEFVCCPLAEESDNVDSADAEEDDSDVWWGGADTDYADGSEDKVVEVAEEEEVAEVEEE
  EADDDEDDEDGDEVEEEAEEPYEEATERTTSIATTTTTTTESVEEVVREVCSEQAETGPC
  RAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVCGSAMSQSLLKTTQEPLARD
  PVKLPTTAASTPDAVDKYLETPGDENEHAHFQKAKERLEAKHRERMSQVMREWEEAERQA
  KNLPKADKKAVIQHFQEKVESLEQEAANERQQLVETHMARVEAMLNDRRRLALENYITAL
  QAVPPRPRHVFNMLKKYVRAEQKDRQHTLKHFEHVRMVDPKKAAQIRSQVMTHLRVIYER
  MNQSLSLLYNVPAVAEEIQDEVDELLQKEQNYSDDVLANMISEPRISYGNDALMPSLTET
  KTTVELLPVNGEFSLDDLQPWHSFGADSVPANTENEVEPVDARPAADRGLTTRPGSGLTN
  IKTEEISEVKMDAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITL
  VMLKKKQYTSIHHGVVEVDAAVTPEERHLSKMQQNGYENPTYKFFEQMQN
• Function: 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. 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. Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis.
• KEGG Pathway:
  Serotonergic synapse (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-MON

Molecular Interaction Atlas (MIA) of This DTT

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ALN-APP	DME8BPN	Alzheimer disease	8A20	Phase 1	[2]

References

• [1] Expression of BC1 Impairs Spatial Learning and Memory in Alzheimer's Disease Via APP Translation. Mol Neurobiol. 2018 Jul;55(7):6007-6020.
• [2] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2023. Adis Insight