Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-beta precursor protein and amyloidogenic A beta peptide formation

The amyloid-beta precursor protein (APP) is directly and efficiently cleave d by caspases during apoptosis, resulting in elevated amyloid-beta (A beta) peptide formation. The predominant site of caspase-mediated proteolysis is within the cytoplasmic tail of APP, and cleavage at this site occurs in hi ppocampal neurons in vivo following acute excitotoxic or ischemic brain inj ury. Caspase-3 is the predominant caspase involved in APP cleavage, consist ent with its marked elevation in dying neurons of Alzheimer's disease brain s and colocalization of its APP cleavage product with A beta in senile plaq ues. Caspases thus appear to play a dual role in proteolytic processing of APP and the resulting propensity for A beta peptide formation, as well as i n the ultimate apoptotic death of neurons in Alzheimer's disease.