In Alzheimer's disease pathogenesis, amyloid-beta (Abeta) plaques form from sequential cleavage of amyloid precursor protein (APP). In the amyloidogenic pathway, APP is first cleaved by beta-secretase (BACE1), then by gamma-secretase. The critical difference between the amyloidogenic and non-amyloidogenic pathways lies in which of the following?

• A In the non-amyloidogenic pathway, alpha-secretase cleaves within the Abeta domain (at Lys16), preventing Abeta generation; amyloidogenic pathway preserves the full Abeta sequence for gamma-secretase to release Abeta40/42 ✓
• B In the amyloidogenic pathway, BACE2 rather than BACE1 initiates cleavage of APP
• C Gamma-secretase is replaced by caspase-3 in the amyloidogenic pathway
• D The non-amyloidogenic pathway requires presenilin-1 mutations to generate sAPP-alpha fragment

Explanation

APP cleavage pathways: Non-amyloidogenic: alpha-secretase (ADAM10, ADAM17) cleaves APP within the Abeta domain at the Lys16-Leu17 bond, generating sAPP-alpha (soluble neuroprotective) and CTF-alpha; subsequent gamma-secretase cleavage of CTF-alpha produces p3 fragment (harmless). This pathway PREVENTS Abeta formation because the Abeta sequence is severed. Amyloidogenic: BACE1 (beta-secretase) cleaves APP at the N-terminus of the Abeta domain, generating sAPP-beta and CTF-beta. Gamma-secretase then cleaves CTF-beta to release either Abeta40 (more common) or Abeta42 (more amyloidogenic/aggregation-prone, increased in presenilin-1/2 mutations). Presenilin-1 and -2 are catalytic subunits of gamma-secretase; FAD-associated presenilin mutations shift the Abeta42/Abeta40 ratio toward Abeta42.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.