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

Abstract：

:Amyloid-β (Aβ), 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 Aβ can induce neuronal apoptosis via caspase-3 activation. Here, we performed biochemical and in silico studies to investigate possible direct effect of Aβ on caspase-3 to understand the molecular mechanism of the interaction between Aβ and caspase-3. We found that Aβ conformers can specifically and directly sequester caspase-3 activity in which freshly prepared Aβ42 is the most potent. The inhibition is noncompetitive, and the C-terminal region of Aβ plays an important role in sequestration. The binding of Aβ 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 Aβ42 exhibits a higher binding affinity than Aβ40 and the hydrophobic C-terminal region plays a key role in the caspase-Aβ interaction. Overall, our study describes a novel mechanism demonstrating that Aβ sequesters caspase-3 activity via direct interaction and facilitates future therapeutic development in AD.

journal_name

ACS Chem Neurosci

journal_title

ACS chemical neuroscience

authors

Chang YJ,Linh NH,Shih YH,Yu HM,Li MS,Chen YR

doi

10.1021/acschemneuro.6b00049

subject

Has Abstract

pub_date

2016-08-17 00:00:00

pages

1097-106

issue

8

issn

1948-7193

journal_volume

7

pub_type

杂志文章

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