In Alzheimer's disease, the amyloid cascade hypothesis posits that Aβ42 peptide accumulation is the primary pathogenic event. Which enzyme generates Aβ42, and why is Aβ42 more amyloidogenic than Aβ40?

• A Alpha-secretase cleaves APP within the Aβ sequence, generating a soluble sAPPα fragment; mutations in alpha-secretase cause AD by producing excess Aβ42
• B Beta-secretase (BACE1) cleaves APP at the N-terminus of Aβ to generate C99; gamma-secretase (presenilin complex) then cleaves C99 at position 40 or 42. Aβ42 has two extra hydrophobic residues at its C-terminus (Ile41, Ala42), making it nucleate aggregation faster, form more stable fibrils, and deposit preferentially in plaques compared to Aβ40 ✓
• C Gamma-secretase cleaves APP first at the ectodomain to generate sAPPβ; beta-secretase then cleaves the residual fragment to generate Aβ42 exclusively
• D Both Aβ40 and Aβ42 are generated exclusively by alpha-secretase; BACE1 is responsible only for Notch processing

Explanation

APP (amyloid precursor protein) undergoes sequential proteolytic processing. In the amyloidogenic pathway, BACE1 (beta-secretase) cleaves APP to release sAPPβ and retains the C-terminal fragment C99. Gamma-secretase (a presenilin-1/2-containing protease complex) cleaves C99 at variable sites, producing Aβ40 (main product, ~90%) or Aβ42 (~10%). Aβ42 carries two additional hydrophobic residues at its C-terminus, which dramatically accelerates its self-aggregation into oligomers and fibrils (nucleation is ~100-fold faster than Aβ40). PS1/PS2 mutations in familial AD shift gamma-secretase cleavage toward Aβ42 production. Soluble Aβ42 oligomers cause synaptic toxicity; insoluble fibrils form neuritic plaques.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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