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Am J Pathol. 2012 Aug;181(2):616-25. doi: 10.1016/j.ajpath.2012.04.020. Epub 2012 Jun 9.

Calpain inhibitor A-705253 mitigates Alzheimer's disease-like pathology and cognitive decline in aged 3xTgAD mice.

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  • 1Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California 92697-4545, USA.

Abstract

Calpains are cysteine proteinases that selectively cleave proteins in response to calcium signals. Exacerbated activation of calpain has been implicated as a major component in the signaling cascade that leads to β-amyloid (Aβ) production and tau hyperphosphorylation in Alzheimer's disease (AD). In this study, we analyzed the potential therapeutic efficacy of inhibiting the activation of calpain by a novel calpain inhibitor in aged 3xTgAD mice with well-established cognitive impairment, plaques, and tangles. The administration of a novel inhibitor of calpain, A-705253, attenuated cognitive impairment and synaptic dysfunction in a dose-dependent manner in 3xTgAD mice. Inhibition of calpain lowered Aβ(40) and Aβ(42) levels in both detergent-soluble and detergent-insoluble fractions and also reduced the total number and size of thioflavin S-positive fibrillar Aβ deposits. Mechanistically, these effects were, in part, explained by a down-regulation of β-secretase 1 (BACE1) and an up-regulation of ATP-binding cassette transporter A1 (ABCA1) expression, which, in turn, contributed to reduced production and increased clearance of Aβ, respectively. Moreover, A-705253 decreased the activation of cyclin-dependent kinase 5 (CDK5) and thereby diminished the hyperphosphorylation of tau. Finally, blockage of calpain activation reduced the astrocytic and microglial responses associated with AD-like pathological characteristics in aged 3xTgAD mice. Our data provide relevant functional and molecular insights into the beneficial therapeutic effects of inhibiting calpain activation for the management of AD.

Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

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PMID:
22688056
[PubMed - indexed for MEDLINE]
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