Microglia Packed Full of Lipofuscin are Harmful in the Aging Brain

Molecular waste builds up in the lysosomes of long-lived cells such as neurons, and in cells like microglia that ingest extracellular debris in order to clear it from the brain. Lysosomes are the destination for all cellular waste, where materials are broken down to be recycled. While lysosomes are capable of breaking down near every type of biological molecule that they will encounter, some persistent metabolic byproducts pose a problem. Old tissues are characterized by the presence of what is known as lipofuscin, a toxic mix of the various forms of metabolic waste that the lysosome struggles with. When lysosomes become packed with this waste, cells suffer, as the quality control and clearance processes required for optimal function falter.

In today's research materials, scientists provide evidence for lipofuscin in microglia, the innate immune cells of the brain, to be problematic. This presence of lipofuscin increases with age, and appears to meaningfully contribute to the observed age-related dysfunctions of these cells. Relatedly, activation and inflammatory signaling of microglia is implicated in the onset and progression of neurodegenerative conditions. When researchers clear microglia from the brain, there are improvements - this has been demonstrated numerous times in recent years. Since all microglia are cleared, however, it is hard to claim that benefits result from removal of lipofuscin-bearing microglia versus other subpopulations of these cells.

Fresh understanding of ageing in the brain offers hope for treating neurological diseases

"As the brain ages, fat molecules, cholesterol crystals, metals, and misfolded proteins build up inside autofluorescent microglia, which increase their autofluorescence as a result. Unfortunately, this accumulation of cellular debris also makes it harder for the microglia to perform their essential garbage collection tasks in the brain and to prevent neurological injury and neurodegenerative disease."

"In this study we found - in aged animals - that these microglia adopt a unique, dysfunctional state, which has a number of problematic impacts. For example, there is an increase in cellular stress and damage, an accumulation of fats and iron, alterations to metabolic processes and an increase in production of molecules that overstimulate the immune response. Increasing evidence now suggests that the accumulation of autofluorescent microglia contributes to diseases of ageing and neurodegeneration. If these sub-populations of microglia are highly inflammatory and damaging to the brain, then targeting them could be a new strategy for treating aging-related diseases."

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

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 (older than 18 months) 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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