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A beta mediates F-actin disassembly in dendritic spines leading to cognitive deficits in Alzheimer's disease

Kommaddi, Reddy Peera and Das, Debajyoti and Karunakaran, Smitha and Nanguneri, Siddharth and Bapat, Deepti and Ray, Ajit and Shaw, Eisha and Bennett, David A and Nair, Deepak and Ravindranath, Vijayalakshmi (2018) A beta mediates F-actin disassembly in dendritic spines leading to cognitive deficits in Alzheimer's disease. In: JOURNAL OF NEUROSCIENCE, 38 (5). pp. 1085-1099.

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Official URL: http://dx.doi.org/10.1523/JNEUROSCI.2127-17.2017

Abstract

Dendritic spine loss is recognized as an early feature of Alzheimer's disease (AD), but the underlying mechanisms are poorly understood. Dendritic spine structure is defined by filamentous actin (F-actin) and we observed depolymerization of synaptosomal F-actin accompanied by increased globular-actin (G-actin) at as early as 1 month of age in a mouse model of AD(APPswe/PS1 Delta E9, male mice). This led to recall deficit after contextual fear conditioning (cFC) at 2 months of age in APPswe/PS1 Delta E9 male mice, which could be reversed by the actin-polymerizing agent jasplakinolide. Further, the F-actin-depolymerizing agent latrunculin induced recall deficit after cFC in WT mice, indicating the importance of maintaining F-/G-actin equilibrium for optimal behavioral response. Using direct stochastic optical reconstruction microscopy (dSTORM), we show that F-actin depolymerization in spines leads to a breakdown of the nano-organization of outwardly radiating F-actin rods in cortical neurons from APPswe/PS1 Delta E9 mice. Our results demonstrate that synaptic dysfunction seen as F-actin disassembly occurs very early, before onset of pathological hallmarks in AD mice, and contributes to behavioral dysfunction, indicating that depolymerization of F-actin is causal and not consequent to decreased spine density. Further, we observed decreased synaptosomal F-actin levels in postmortem brain from mild cognitive impairment and AD patients compared with subjects with normal cognition. F-actin decrease correlated inversely with increasing AD pathology (Braak score, A beta load, and tangle density) and directly with performance in episodic and working memory tasks, suggesting its role in human disease pathogenesis and progression.

Item Type: Journal Article
Additional Information: Copy right for this article belongs to the SOC NEUROSCIENCE, 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA
Department/Centre: Division of Biological Sciences > Centre for Neuroscience
Depositing User: Id for Latest eprints
Date Deposited: 02 Mar 2018 15:04
Last Modified: 02 Mar 2018 15:04
URI: http://eprints.iisc.ac.in/id/eprint/58944

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