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Glutaredoxin1 Diminishes Amyloid Beta-Mediated Oxidation of F-Actin and Reverses Cognitive Deficits in an Alzheimer's Disease Mouse Model

Kommaddi, Reddy Peera and Tomar, Deepika Singh and Karunakaran, Smitha and Bapat, Deepti and Nanguneri, Siddharth and Ray, Ajit and Schneider, Bernard L. and Nair, Deepak and Ravindranath, Vijayalakshmi (2019) Glutaredoxin1 Diminishes Amyloid Beta-Mediated Oxidation of F-Actin and Reverses Cognitive Deficits in an Alzheimer's Disease Mouse Model. In: ANTIOXIDANTS & REDOX SIGNALING, 31 (18). pp. 1321-1338.

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Official URL: http://doi.org/10.1089/ars.2019.7754

Abstract

Aims: Reactive oxygen species (ROS) generated during Alzheimer's disease (AD) pathogenesis through multiple sources are implicated in synaptic pathology observed in the disease. We have previously shown F-actin disassembly in dendritic spines in early AD (34). The actin cytoskeleton can be oxidatively modified resulting in altered F-actin dynamics. Therefore, we investigated whether disruption of redox signaling could contribute to actin network disassembly and downstream effects in the amyloid precursor protein/presenilin-1 double transgenic (APP/PS1) mouse model of AD. Results: Synaptosomal preparations from 1-month-old APP/PS1 mice showed an increase in ROS levels, coupled with a decrease in the reduced form of F-actin and increase in glutathionylated synaptosomal actin. Furthermore, synaptic glutaredoxin 1 (Grx1) and thioredoxin levels were found to be lowered. Overexpressing Grx1 in the brains of these mice not only reversed F-actin loss seen in APP/PS1 mice but also restored memory recall after contextual fear conditioning. F-actin levels and F-actin nanoarchitecture in spines were also stabilized by Grx1 overexpression in APP/PS1 primary cortical neurons, indicating that glutathionylation of F-actin is a critical event in early pathogenesis of AD, which leads to spine loss. Innovation: Loss of thiol/disulfide oxidoreductases in the synapse along with increase in ROS can render F-actin nanoarchitecture susceptible to oxidative modifications in AD. Conclusions: Our findings provide novel evidence that altered redox signaling in the form of S-glutathionylation and reduced Grx1 levels can lead to synaptic dysfunction during AD pathogenesis by directly disrupting the F-actin nanoarchitecture in spines. Increasing Grx1 levels is a potential target for novel disease-modifying therapies for AD.

Item Type: Journal Article
Additional Information: Copyright for this article belongs to Mary Ann Liebert, Inc.
Keywords: Grx1; oxidation; reactive oxygen species; neurodegenerative disease; cytoskeleton; cognition
Department/Centre: Division of Biological Sciences > Centre for Neuroscience
Autonomous Societies / Centres > Centre for Brain Research
Depositing User: Id for Latest eprints
Date Deposited: 27 Feb 2020 10:28
Last Modified: 27 Feb 2020 10:28
URI: http://eprints.iisc.ac.in/id/eprint/63996

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