Alzheimer's Amyloid-β Sequesters Caspase-3 in Vitro via Its C-Terminal Tail

Amyloid-beta (A beta), the main constituent in senile plaques found in the brain of patients with Alzheimer's disease (AD), is considered as a causative factor in AD pathogenesis. The clinical examination of the brains of patients with AD has demonstrated that caspase-3 colocalizes with senile plaques. Cellular studies have shown that A beta can induce neuronal apoptosis via caspase-3 activation. Here, we performed biochemical and in silico studies to investigate possible direct effect of A beta on caspase-3 to understand the molecular mechanism of the interaction between A beta and caspase-3. We found that A beta conformers can specifically and directly sequester caspase-3 activity in which freshly prepared A beta 42 is the most potent. The inhibition is noncompetitive, and the C-terminal region of A beta plays an important role in sequestration. The binding of A beta to caspase-3 was examined by cross-linking and proteolysis and by docking and all-atom molecular dynamic simulations. Experimental and in silico results revealed that A beta 42 exhibits a higher binding affinity than A beta 40 and the hydrophobic C-terminal region plays a key role in the caspase-A beta interaction. Overall, our study describes a novel mechanism demonstrating that A beta sequesters caspase-3 activity via direct interaction and facilitates future therapeutic development in AD.