Dysfunctional γ-Secretase in Familial Alzheimer’s Disease

Genetics strongly implicate the amyloid β-peptide (Aβ) in the pathogenesis of Alzheimer’s disease. Dominant missense mutation in the presenilins and the amyloid precursor protein (APP) cause early-onset familial Alzheimer’s disease (FAD). As presenilin is the catalytic component of the γ-secretase protease complex that produces Aβ from APP, mutation of the enzyme or substrate that produce Aβ leads to FAD. However, the mechanism by which presenilin mutations cause FAD has been controversial, with gain of function and loss of function offered as binary choices. This overview will instead present the case that presenilins are dysfunctional in FAD. γ-Secretase is a multi-functional enzyme that proteolyzes the APP transmembrane domain in a complex and processive manner. Reduction in a specific function—the carboxypeptidase trimming of initially formed long Aβ peptides containing most of the transmembrane domain to shorter secreted forms—is an emerging common feature of FAD-mutant γ-secretase complexes.