Brain injury accelerates the onset of a reversible age-related microglial phenotype associated with inflammatory neurodegeneration

Traumatic 610 Brain Inbred C57BL Lipids Mice, Inbred C57BL Mice Phenotype Neurology Brain Injuries 616 Brain Injuries, Traumatic Medical Specialties Medicine and Health Sciences Animals Microglia Neuroscience
DOI: 10.1126/sciadv.add1101 Publication Date: 2023-03-08T18:57:16Z
ABSTRACT
Lipofuscin is an autofluorescent (AF) pigment formed by lipids and misfolded proteins, which accumulates in postmitotic cells with advanced age. Here, we immunophenotyped microglia in the brain of old C57BL/6 mice (>18 months old) and demonstrate that in comparison to young mice, one-third of old microglia are AF, characterized by profound changes in lipid and iron content, phagocytic activity, and oxidative stress. Pharmacological depletion of microglia in old mice eliminated the AF microglia following repopulation and reversed microglial dysfunction. Age-related neurological deficits and neurodegeneration after traumatic brain injury (TBI) were attenuated in old mice lacking AF microglia. Furthermore, increased phagocytic activity, lysosomal burden, and lipid accumulation in microglia persisted for up to 1 year after TBI, were modified by APOE4 genotype, and chronically driven by phagocyte-mediated oxidative stress. Thus, AF may reflect a pathological state in aging microglia associated with increased phagocytosis of neurons and myelin and inflammatory neurodegeneration that can be further accelerated by TBI.
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