APP - Amyloid Precursor Protein (Human) Notes

Overview

Human APP (P05067) is the ortholog of mouse App. The biology is essentially identical - a type I transmembrane protein that undergoes regulated intramembrane proteolysis (RIP) to produce multiple bioactive fragments.

Key difference from mouse: Human APP is directly relevant to Alzheimer's disease pathology. The human Abeta sequence differs slightly from mouse, and human Abeta is more prone to aggregation. AD mouse models often use humanized APP.

Splice Isoforms

Isoform UniProt Length Domains Expression
APP770 P05067-1 770 AA KPI + OX-2 Peripheral, microglia
APP751 P05067-6 751 AA KPI only Peripheral tissues
APP695 P05067-4 695 AA No KPI Neuronal (predominant in brain)
L-APP677 P05067-3 677 AA No KPI Leukocytes
APP305 P05067-2 305 AA Truncated Limited data

Cleavage Products

Same as mouse - see mouse App notes for details:
- sAPPalpha (neuroprotective)
- sAPPbeta (less neurotrophic, DR6 binding)
- Abeta40/42 (neurotoxic, AD pathogenic)
- AICD (nuclear signaling)
- N-APP (axon pruning via DR6)

Familial AD Mutations

Human APP mutations cause familial Alzheimer's disease by increasing Abeta42/Abeta40 ratio:

Mutation Position Effect
Swedish K670N/M671L Increases total Abeta
London V717I Increases Abeta42/40 ratio
Flemish A692G Increases Abeta aggregation
Arctic E693G Increases protofibril formation
Iowa D694N Increases cerebral amyloid angiopathy

Key Human-Specific Points

  1. Human Abeta sequence at positions 5, 10, 13 differs from rodent - more aggregation-prone
  2. Most AD mouse models use human APP transgenes
  3. Down syndrome (trisomy 21) causes AD due to APP gene triplication on chromosome 21
  4. Protective mutation (A673T, "Icelandic") reduces Abeta production and AD risk

References

2026-06-20 Second-Pass Review Notes

Second-pass cleanup separated normal APP biology from Alzheimer disease mechanism
context. The review description now emphasizes full-length APP receptor/adhesion
activity, regulated proteolytic processing, APP751/770 KPI-domain protease
inhibitor activity, and copper/metal-binding biology.

Key evidence anchors:
- UniProt supports full-length APP receptor/adhesion biology: "Functions as a
cell surface receptor" and "neuronal adhesion and axonogenesis"
[file:human/APP/APP-uniprot.txt].
- UniProt supports APP-family synaptic adhesion output: "promotes synaptogenesis"
[file:human/APP/APP-uniprot.txt].
- UniProt supports copper/metal biology: "Extracellular binding and reduction of
copper" and "Amyloid-beta peptides are lipophilic metal chelators"
[file:human/APP/APP-uniprot.txt].

Second-pass curation decisions:
- Added NEW review entries for GO:0098631 cell adhesion mediator activity,
GO:0050839 cell adhesion molecule binding, and GO:0005507 copper ion binding
so authored core-function terms are represented in the annotation block.
- Harmonized GO:1900272 negative regulation of long-term synaptic potentiation
as KEEP_AS_NON_CORE. The evidence is credible for amyloid-beta cleavage-product
effects on plasticity, but this is not the core evolved function of full-length
APP.
- Harmonized broad GO:0051247 positive regulation of protein metabolic process
and GO:0070555 response to interleukin-1 as MARK_AS_OVER_ANNOTATED.
- Added knowledge-gap questions and suggested experiments focused on evolved
in-vivo APP isoform, fragment, adhesion, trophic-signaling, metal-binding, and
intracellular-domain biology.