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.
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Authors | Rodrigo Medeiros, Masashi Kitazawa, Meredith A Chabrier, David Cheng, David Baglietto-Vargas, Andreas Kling, Achim Moeller, Kim N Green, Frank M LaFerla |
Journal | The American journal of pathology
(Am J Pathol)
Vol. 181
Issue 2
Pg. 616-25
(Aug 2012)
ISSN: 1525-2191 [Electronic] United States |
PMID | 22688056
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- A-705253
- ABCA1 protein, human
- ATP Binding Cassette Transporter 1
- ATP-Binding Cassette Transporters
- Amyloid beta-Peptides
- Benzamides
- Glycoproteins
- calpain inhibitors
- tau Proteins
- Cyclin-Dependent Kinase 5
- Amyloid Precursor Protein Secretases
- Aspartic Acid Endopeptidases
- Bace1 protein, mouse
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Topics |
- ATP Binding Cassette Transporter 1
- ATP-Binding Cassette Transporters
(metabolism)
- Aging
(drug effects, pathology)
- Alzheimer Disease
(drug therapy, enzymology, pathology, physiopathology)
- Amyloid Precursor Protein Secretases
(metabolism)
- Amyloid beta-Peptides
(metabolism)
- Animals
- Aspartic Acid Endopeptidases
(metabolism)
- Benzamides
(pharmacology, therapeutic use)
- Cognition
(drug effects)
- Cyclin-Dependent Kinase 5
(antagonists & inhibitors, metabolism)
- Enzyme Activation
(drug effects)
- Glycoproteins
(pharmacology, therapeutic use)
- Humans
- Inflammation
(complications, drug therapy, pathology)
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Nervous System
(drug effects, pathology)
- Phosphorylation
(drug effects)
- tau Proteins
(metabolism)
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