Gamma-secretase mediated cleavage of the β-secretase processed β-amyloid precursor protein leads to the extracellular release of Aβ40 and Aβ42, the more amyloidogenic form of the β-amyloid peptide, which subsequently forms the amyloid-plaques in the brains of Alzheimer's Disease patients. Mutations in β-amyloid precursor protein, Presenilin-1 and Presenilin-2 associated with forms of Familial Alzheimer's Disease (FAD) increase release of Aβ42, suggesting that FAD may directly result from increased γ-secretase activity. Here we show that FAD mutations clustered near the sites of γ-secretase cleavage actually decrease γ-secretase mediated cleavage of the β-amyloid precursor protein, as assessed by release of the intracellular fragment (CTFγ). Concordantly, Presenilin-1 mutations that result in Alzheimer's Disease also decrease the release of CTFγ. These data indicate that Alzheimer's mutations in β-amyloid precursor protein and Presenilin-1 may be categorized as loss of function mutations, which would result in decreases in signaling associated with normal transcriptional regulation by β-amyloid precursor protein. |