In Alzheimer disease, the process of amyloid beta (Aβ) peptide generation from amyloid precursor protein (APP) involves sequential cleavage by two enzymes. The amyloidogenic pathway uses:

• A Alpha-secretase then gamma-secretase (non-amyloidogenic)
• B Caspase-3 then cathepsin D, generating N-truncated Aβ fragments
• C Beta-secretase (BACE1) then gamma-secretase, generating Aβ40/42 ✓
• D Alpha-secretase then beta-secretase, releasing soluble sAPPβ

Explanation

APP is cleaved in two competing pathways: (1) Non-amyloidogenic: alpha-secretase cleaves within the Aβ domain (releasing sAPPα), preventing intact Aβ generation; (2) Amyloidogenic: beta-secretase (BACE1) cleaves APP at the N-terminus of the Aβ sequence (releasing sAPPβ), followed by gamma-secretase complex (presenilin 1/2 as catalytic subunit) cleaving within the transmembrane domain, releasing Aβ40 and Aβ42. Aβ42 is more aggregation-prone and forms senile plaques. Presenilin 1/2 mutations (familial AD) shift gamma-secretase cleavage 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.