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

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.

Age-related changes in plasma extracellular vesicles influence neuroinflammation in the brain and neurological outcome after traumatic spinal cord injury

“…Microglial phagocytosis was measured by intracellular detection of neuronal antigens, including Thy1, NeuN, and Synaptophysin. Consistent with our previous reports [49,50], microglial cells in aged groups showed higher levels of these neuronal markers with significant group effect of age, confirming increased activities of microglial phagocytosis in aged brain (Fig. 6a-c).…”

“…The SR test was performed using a three-chambered rectangular apparatus (60 x 40 x 23 cm) made of transparent Plexiglas [49]. It was divided into three equal chambers by two walls that each had a semicircular hole of 5 cm diameter in the bottom for free access to each chamber.…”

“…Leukocytes were first gated using a splenocyte reference (SSC-A vs FSC-A). Singlets were gated (FSC-H vs FSC-W), and live cells were gated based on Zombie Aqua exclusion (SSC-A vs Zombie Aqua-Bv510) [49,50].…”

“…Aging microglia show altered physiology, with evidence of cellular senescence and immune dysfunction [51]. We recently reported that a sub-population of microglia in older mice adopted a unique dysfunctional phenotype defined by changes in phagocytosis, oxidative stress, lysosomal content and autophagy, lipid and iron accumulation, metabolic alterations, pro-inflammatory cytokine production, and senescent-like features [49,50]. However, whether age-related alterations in microglial and immune function are exacerbated in the brain after SCI is unknown.…”

Imaging Brain Injury in Former National Football League Players

“…Sports-related, repeated brain injury is associated with varied neurologic and psychiatric sequelae . The observed association between repeated, mild traumatic brain injury (mTBI) and cognitive impairment may be mediated by microglia, the brain’s immune cells . Tracking the microglial response to brain injury is possible using positron emission tomography (PET) with a radiotracer targeting the translocator protein 18 kDa (TSPO) .…”