App - Amyloid Precursor Protein Notes

Overview

APP is a paradigm for regulated intramembrane proteolysis (RIP) - a type I transmembrane protein processed by multiple secretases to generate fragments with distinct biological activities. APP biology is central to Alzheimer's disease pathogenesis.

Dual Complexity: Splicing + Proteolysis

APP has BOTH alternative splicing AND proteolytic processing, making it more complex than POMC:

Alternative Splice Isoforms

Isoform UniProt Length KPI Domain Tissue
APP695 P12023-4 695 AA No Neuronal (predominant in brain)
APP751 P12023-2 751 AA Yes Peripheral, some neurons
APP770 P12023-1 770 AA Yes + OX-2 Peripheral, microglia
APP-L P12023-3 733 AA Yes Leukocytes

The KPI (Kunitz Protease Inhibitor) domain is encoded by exon 7 - APP695 skips this exon.

Functional significance:
- APP695 is the predominant neuronal form - relevant for synaptic function
- KPI-containing isoforms (751/770) may have protease inhibitor functions
- The ratio of isoforms changes in AD and with aging

Proteolytic Cleavage Products

Two competing pathways:

Non-amyloidogenic pathway (alpha-secretase, ADAM10/17):

APP → sAPPα + C83 (α-CTF)
C83 → p3 + AICD (via gamma-secretase)

Amyloidogenic pathway (beta-secretase, BACE1):

APP → sAPPβ + C99 (β-CTF)
C99 → Aβ40/Aβ42 + AICD (via gamma-secretase)

Cleavage Products (from UniProt)

Product Residues PRO ID Function
N-APP 18-286 PRO_0000000088 DR6 binding, axon pruning
sAPPα 18-687 PRO_0000000089 Neuroprotective, neurotrophic
sAPPβ 18-671 PRO_0000000090 Less neurotrophic than sAPPα
C99 (β-CTF) 672-770 PRO_0000000091 Precursor to Aβ
C83 (α-CTF) 688-770 PRO_0000000092 Non-amyloidogenic pathway
Aβ42 672-713 PRO_0000000093 Pathogenic - aggregates in AD
Aβ40 672-711 PRO_0000000094 Major Aβ species
p3 688-713/711 - Non-amyloidogenic fragment
AICD 714/712-770 PRO_0000000095 Nuclear signaling (controversial)

Key Functional Differences

  1. sAPPα vs sAPPβ: sAPPα is neuroprotective and neurotrophic; sAPPβ has 10-100x less activity and may be pro-apoptotic via DR6 binding

  2. Aβ40 vs Aβ42: Aβ42 is more aggregation-prone and toxic; Aβ42/Aβ40 ratio is critical for AD pathogenesis

  3. AICD: Proposed transcription factor that translocates to nucleus with Fe65/Tip60 - regulates genes including EGFR, p53, KAI1, GSK3B (controversial, may be artifact)

  4. N-APP: The N-terminal fragment binds DR6 and triggers axon degeneration - relevant for developmental pruning and possibly neurodegeneration

GO Annotation Challenges

  1. Pathway-specific functions: "Positive regulation of neuron death" applies to Aβ, but "neuroprotection" applies to sAPPα - both from same gene

  2. Isoform specificity: KPI-containing isoforms have protease inhibitor activity that APP695 lacks

  3. Cleavage product specificity: Most experimental work uses specific fragments, but annotations are at gene level

  4. Full-length APP functions:

  5. Cell adhesion
  6. Copper/zinc binding
  7. Heparin binding
  8. Synapse formation
  9. Axon guidance

Key References

Questions for Curation

  1. How to handle annotations that clearly apply only to Aβ vs sAPP vs full-length?
  2. Should we use functional_isoforms for both splice variants AND cleavage products?
  3. How to handle the controversial AICD transcription factor activity?