In Alzheimer disease, the pathological cascade hypothesis implicates amyloid-β (Aβ) as the initiating event. BACE1 (β-secretase) and γ-secretase are the enzymes generating Aβ from APP. Normally, α-secretase cleaves APP within the Aβ sequence, preventing Aβ formation. This normal cleavage produces:
- A Full-length Aβ42 peptide
- B Soluble sAPPα fragment (neuroprotective) and a membrane-bound C83 stub ✓
- C Phosphorylated tau leading to neurofibrillary tangles
- D Presenilin-1 activation in the gamma secretase complex
Explanation
The amyloid precursor protein (APP) is processed by two competing pathways. The non-amyloidogenic pathway uses α-secretase (ADAM10) to cleave within the Aβ domain, generating soluble sAPPα (neurotrophic, memory-enhancing) and membrane-bound C83, which is then cleaved by γ-secretase to a harmless p3 fragment. This pathway precludes Aβ generation. The amyloidogenic pathway uses BACE1 (β-secretase) generating sAPPβ and C99, which γ-secretase cleaves to produce Aβ40 or Aβ42. Aβ42 is more amyloidogenic and aggregates into toxic oligomers and plaques. Mutations in APP, PS1, PS2 shift processing toward Aβ42 production.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
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Written and medically reviewed by the StethoPrep medical team.