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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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 |
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Publication: | JOURNAL OF NEUROSCIENCE |
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 |
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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