γ-Secretase Modulators and Presenilin 1 Mutants Act Differently on Presenilin/γ-Secretase Function to Cleave Aβ42 and Aβ43

Deciphering the mechanism by which the relative A beta 42(43) to total A beta ratio is regulated is central to understanding Alzheimer disease (AD) etiology; however, the mechanisms underlying changes in the A beta 42(43) ratio caused by familial mutations and gamma-secretase modulators (GSMs) are unclear. Here, we show in vitro and in living cells that presenilin (PS)/gamma-secretase cleaves A beta 42 into A beta 38, and A beta 43 into A beta 40 or A beta 38. Approximately 40% of A beta 38 is derived from A beta 43. A beta 42(43) cleavage is involved in the regulation of the A beta 42(43) ratio in living cells. GSMs increase the cleavage of PS/gamma-secretase-bound A beta 42 (increase k(cat)) and slow its dissociation from the enzyme (decrease k(b)), whereas PS1 mutants and inverse GSMs show the opposite effects. Therefore, we suggest a concept to describe the A beta 42(43) production process and propose how GSMs act, and we suggest that a loss of PS/gamma-secretase function to cleave A beta 42(43) may initiate AD and might represent a therapeutic target.