Alzheimer's Disease-Linked Mutations in Presenilin-1 Result in a Drastic Loss of Activity in Purified γ-Secretase Complexes

摘要: Background: Mutations linked to early onset, familial forms of Alzheimer's disease (FAD) are found most frequently in PSEN1, the gene encoding presenilin-1 (PS1). Together with nicastrin (NCT), anterior pharynx-defective protein 1 (APH1), and presenilin enhancer 2 (PEN2), catalytic subunit PS1 constitutes core c-secretase complex contributes proteolysis amyloid precursor (APP) into amyloid-beta (A beta) peptides. Although there is a growing consensus that FAD-linked mutations affect Ab production by enhancing A beta 1-42/A 1-40 ratio, it remains unclear whether how they generation APP intracellular domain (AICD). Moreover, controversy exists as exert their effects different experimental systems, either increasing 1-42 production, decreasing or both. Because could be explained heterogeneity composition gamma-secretase, we purified homogeneity complexes made human NCT, APH1aL, PEN2, pathogenic mutants L166P, Delta E9, P436Q.