A 70-year-old woman with slowly progressive dementia for 3 years. At autopsy, gross examination shows cortical atrophy predominantly in the temporal and parietal lobes with 'knife-blade' gyri. Histology reveals senile plaques (amyloid-beta) and neurofibrillary tangles (hyperphosphorylated tau). Which enzyme generates the amyloid-beta peptide that aggregates in senile plaques?

• A Beta-secretase (BACE1) followed by gamma-secretase (presenilin complex) — amyloidogenic sequential cleavage ✓
• B Alpha-secretase — non-amyloidogenic cleavage within the Abeta domain
• C Gamma-secretase alone — single transmembrane cleavage releasing full-length APP
• D Caspase-3 cleaving APP during apoptotic neuronal death generates Abeta

Explanation

Amyloid-beta (Abeta) is generated by sequential amyloidogenic processing of amyloid precursor protein (APP): first, beta-secretase (BACE1) cleaves APP at the extracellular/luminal domain generating a C99 fragment; then gamma-secretase (a presenilin-containing complex) cleaves within the transmembrane domain to release Abeta40 or Abeta42. Presenilin-1 and -2 mutations in familial AD increase the Abeta42/40 ratio, as Abeta42 is more aggregation-prone. Alpha-secretase cleaves within the Abeta domain, preventing plaque formation.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.