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Lian Zhao, Jorge Cueva Vargas, Jennifer Liao, Wai T Wong; Microglia Repopulation Ameliorates Aging Phenotypes in Retinal Microglia and Neurons. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2797.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: In the retina, microglia and neurons demonstrate aging-related phenotypic changes, including altered immune function, synaptic disorganization, and decreased neuronal function, which may contribute to age-related neurodegeneration. We previously discovered that microglial repopulation following depletion in young adult mice fully restores the microglial structure and function. As retinal microglia are long-lived cells that accumulate physiological and molecular changes with aging, we investigate if replacement of aged microglia via repopulation can reverse aging phenotypes in microglia and neurons.
Methods: Aged 24-month old C57BL/6J male mice were administered diet containing PLX5622, a CSF1R inhibitor that induces microglial depletion, for 10 days, and then switched to a standard diet to enable microglial repopulation until 27 months of age. They were compared with control young 3-month old and aged 27-month old male mice maintained on standard diets. Mice in the 3 groups were assessed for: (1) structural microglial aging phenotypes in terms of density, morphology, and activation, (2) neuronal aging phenotypes in terms of bipolar and horizontal cell process sprouting, and (3) functional retinal aging phenotypes using ERG.
Results: Microglial repopulation in aged mice induced significant amelioration of multiple aging microglial phenotypes, inducing slightly lower cell densities, and significantly improved process ramification, decreased autofluorescence, and lowered expression of CD68, an activation marker. Neuronal aging phenotypes of aberrant process sprouting and synaptic disorganization in bipolar and horizontal cells were also ameliorated following microglia repopulation. While aged control animals demonstrated progressive declines in dark- and light-adapted ERG amplitudes from 24 to 27 months of age, aged animals following microglial repopulation demonstrated stabilized and improved amplitudes.
Conclusions: Microglial repopulation following depletion in aged retinas results in improvements in structural and functional aging phenotypes in retinal microglia and neurons. The apparent rejuvenation of these phenotypes and their underlying mechanisms may be relevant to translational strategies targeting age-related retinal degeneration.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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