Familial Alzheimer's disease mutations inhibit γ-secretase-mediated liberation of β-amyloid precursor protein carboxy-terminal fragment

Cleavage of the beta-secretase processed beta-amyloid precursor protein by gamma-secretase leads to the extracellular release of A beta 42, the more amyloidogenic form of the beta-amyloid peptide, which subsequently forms the amyloid-plaques diagnostic of Alzheimer's disease. Mutations in beta-amyloid precursor protein (APP), presenilin-1 and presenilin-2 associated with familial Alzheimer's disease (FAD) increase release of A beta 42, suggesting that FAD may directly result from increased gamma-secretase activity. Here, we show that familial Alzheimer's disease mutations clustered near the sites of gamma-secretase cleavage actually decrease gamma-secretase-mediated release of the intracellular fragment of APP (CTF gamma). Concordantly, presenilin-1 mutations that result in Alzheimer's disease also decrease the release of CTF gamma. Mutagenesis of the epsilon cleavage site in APP mimicked the effects of the FAD mutations, both decreasing CTF gamma release and increasing A beta 42 production, suggesting that perturbation of this site may account for the observed decrement in gamma-secretase-mediated proteolysis of APP. As CTF gamma has been implicated in transcriptional activation, these data indicate that decreased signaling and transcriptional regulation resulting from FAD mutations in beta-amyloid precursor protein and presenilin-1 may contribute to the pathology of Alzheimer's disease.