Gervais et al. (1999) found that the amyloid-beta 4A precursor protein (APP; 104760) is directly and efficiently cleaved by caspases during apoptosis, resulting in elevated amyloid-beta peptide formation. The predominant site of caspase-mediated proteolysis is within the cytoplasmic tail of APP, and cleavage at this site occurs in hippocampal neurons in vivo following acute excitotoxic or ischemic brain injury. Caspase-3 is the predominant caspase involved in APP cleavage, consistent with its marked elevation in dying neurons of Alzheimer disease (104300) brains and colocalization of its APP cleavage product with amyloid-beta in senile plaques. Caspases thus appear to play a dual role in proteolytic processing of APP and the resulting propensity for amyloid-beta peptide formation, as well as in the ultimate apoptotic death of neurons in Alzheimer disease (from)
Huntington disease (143100) is a neurodegenerative disorder caused by trinucleotide repeat expansion mutations, which result in extended polyglutamine tracts in the huntingtin protein. Transgenic mice expressing N-terminal mutant huntingtin show intranuclear huntingtin accumulation and develop progressive neurologic symptoms. Inhibiting caspase-1 (147678) can prolong the survival of these HD mice. Li et al. (2000) reported that intranuclear huntingtin induces the activation of caspase-3 and the release of cytochrome c (123970) from mitochondria in cultured cells. As a result, cells expressing intranuclear huntingtin underwent apoptosis. Intranuclear huntingtin increased the expression of caspase-1, which may in turn activate caspase-3 and trigger apoptosis. The authors proposed that the increased level of caspase-1 induced by intranuclear huntingtin may contribute to HD-associated cell death.
