ALTERED MOTILITY OF PLAQUE-ASSOCIATED MICROGLIA IN A MODEL OF ALZHEIMER'S DISEASE

• Type of Material: Article
• Authors: Stefka Gyoneva, Emory University; Sharon Swanger, Emory University; Jing Zhang, Emory University; David Weinshenker, Emory University; Stephen Traynelis, Emory University
• Language: English
• Date: 2016-08-25
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.neuroscience.2016.05.061
• Title of Journal or Parent Work: Neuroscience
• ISSN: 0306-4522
• Volume: 330
• Start Page: 410
• End Page: 420
• Grant/Funding Information: Funding was provided by NINDS NRSA (F31NS076215, S.G.), NIH Pharmacological Sciences institutional training grant (T32GM008602, S.G.), and a pilot grant from the Emory University Alzheimer's Disease Research Center (NIHP50 AG025688, S.F.T.).
• Keywords: CAFFEINE; imaging; IN-VIVO; AMYLOID-BETA LEVELS; Science & Technology; ACTIVATED MICROGLIA; neuroinflammation; TRANSGENIC MICE; Alzheimer's disease; A(2A); ADENOSINE RECEPTORS; adenosine A2A receptors; INFLAMMATION; motility; BRAIN; Neurosciences & Neurology; MOUSE MODEL; microglia; Neurosciences; Life Sciences & Biomedicine
• Research Categories: Health Sciences, Pharmacology; Biology, Genetics; Biology, Neuroscience

Abstract

Alzheimer's disease (AD), the most common form of dementia in the elderly, is characterized by the presence of extracellular plaques composed of amyloid β (Aβ) peptides and intracellular tau aggregates. The plaques are surrounded by microglia, the brain's resident immune cells, which likely participate in the clearance of Aβ by phagocytosis. The microglia that are associated with plaques display an abnormal ameboid morphology and do not respond to tissue damage, in contrast to microglia in healthy brains. Here, we used time lapse confocal microscopy to perform a detailed real-time examination of microglial motility in acute hippocampal brain slices from the 5xFAD mouse model of AD, which was crossed to Cx3cr1 GFP/GFP mice to achieve microglia-specific GFP expression for visualization. During baseline conditions, microglia around plaques appeared hypermotile, moving the processes that were pointing away from plaques at higher speed than microglia not associated with plaques. Yet, neither plaque-associated, nor plaque-free microglia were able to extend processes toward sites of modest mechanical damage. Application of the selective adenosine A2A receptor antagonist preladenant, which restores microglial response to cellular damage in a mouse model of Parkinson's disease, reduced the hypermotility of plaque-associated microglia, but did not restore motility toward damaged cells in slices from 5xFAD mice. Our results suggest that process hypermotility and resistance to A2A antagonism during response to tissue damage may represent unique functional phenotypes of plaque-associated microglia that impair their ability to function properly in the AD brain.