In Alzheimer disease, the amyloid cascade hypothesis posits that Abeta peptide accumulation is the initiating event. Which enzyme is responsible for the rate-limiting step in Abeta generation, and what is the substrate cleavage site?
- A Presenilin-1 (the catalytic subunit of gamma-secretase) is rate-limiting; it cleaves C99 at the epsilon site to release Abeta 42 preferentially in FAD
- B ADAM10 (alpha-secretase) cleaves APP within the Abeta sequence, producing sAPPalpha and C83 that cannot generate Abeta
- C BACE1 (beta-site APP cleaving enzyme 1) cleaves APP at the beta-secretase site (M671-D672), releasing sAPPbeta and membrane-bound C99 fragment for subsequent gamma-secretase cleavage ✓
- D Neprilysin (NEP) is the rate-limiting enzyme; its loss of activity causes Abeta accumulation by impaired degradation rather than enhanced production
Explanation
Amyloid precursor protein (APP) processing begins with BACE1 (beta-secretase/BACE1) cleaving at the ectodomain-transmembrane junction (Asp+1 site, releasing the large N-terminal ectodomain sAPPbeta into CSF and leaving C99 membrane-tethered). This BACE1 step is rate-limiting for Abeta production; BACE1 inhibitors (verubecestat, atabecestat) target this step. C99 is subsequently cleaved by gamma-secretase (presenilin-1/2 complex) at variable sites — cleavage at position 42 generates Abeta42, which is more amyloidogenic and aggregation-prone. Alpha-secretase cleavage (ADAM10) is the non-amyloidogenic pathway, precluding Abeta formation.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
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