Altered motility of plaque-associated microglia in a model of Alzheimer's disease.
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.
Department of Pharmacology, Emory University, Rollins Research Center, 1510 Clifton Road, Atlanta, GA 30322, USA.
Stefka
S
Gyoneva
Department of Pharmacology, Emory University, Rollins Research Center, 1510 Clifton Road, Atlanta, GA 30322, USA.
Sharon A
SA
Swanger
Department of Pharmacology, Emory University, Rollins Research Center, 1510 Clifton Road, Atlanta, GA 30322, USA.
Jing
J
Zhang
Department of Genetics, Emory University, Whitehead Biomedical Research Building, 615 Michael St, Atlanta, GA 30322, USA.
David
D
Weinshenker
Department of Pharmacology, Emory University, Rollins Research Center, 1510 Clifton Road, Atlanta, GA 30322, USA. Electronic address: strayne@emory.edu.
Stephen F
SF
Traynelis
D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D007150:Immunohistochemistry; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D018613:Microscopy, Confocal; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D058225:Plaque, Amyloid / Q000473:pathology / Q000503:physiopathology*; D011743:Pyrimidines / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D046509:Tissue Culture Techniques; D014230:Triazoles / Q000494:pharmacology
D058917:Adenosine A2 Receptor Antagonists; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D014230:Triazoles; C539997:2-(2-furanyl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)-1-piperazinyl)ethyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidine-5-amine
Alzheimer’s disease; adenosine A2A receptors; imaging; microglia; motility; neuroinflammation