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Loss of Beneficial Microglial Function in Alzheimer's Disease

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Posted 22 October 2021 - 07:22 PM

A growing body of evidence suggests that microglia in the brain are important in the progression of neurodegenerative conditions such as Alzheimer's disease. Like the similar macrophages outside the brain, microglia can adopt packages of behavior known as polarizations. M1 is an aggressive, inflammatory polarization suited to hunting pathogens, while M2 is an anti-inflammatory, pro-regenerative polarization suited to the maintenance and repair of tissue. This taxonomy is an oversimplification of a more complex reality, but it is a useful model when thinking about how and why microglia may contribute to neurodegeneration.

Chronic inflammation in brain tissue is a feature of neurodegenerative conditions, and activated M1 microglia help to sustain that inflammatory state. This contribution to chronic inflammation is particularly the case when microglia become senescent, and studies in animal models have shown benefits to result from the use of senolytic therapies that selectively destroy senescent cells in the brain. Further, if more of the microglial population is M1, then it is likely that fewer microglia are undertaking necessary M2 activities. With that in mind, today's open access paper provides supporting evidence for the loss of M2 macrophage activities in neurodegenerative disease.

What can be done about this? One possible approach is to clear the entire microglial cell population in the brain, and let it reconstitute. That replacement happens quite rapidly, and the new microglia are less problematic than the originals, at least for a time. Researchers have used CSF1R inhibitors to achieve clearance of microglia in mice, and shown that it helps in models of Alzheimer's disease. It remains to be seen as to whether and when this will be attempted in human patients.

Microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer's disease

Microglia are the resident innate immune cells of the central nervous system (CNS), and are key players to mediate neuroinflammation, playing critical roles in the recognition and clearance of in Alzheimer's disease (AD). The activation phenotype of microglia was previously classified by the expression pattern of cytokines in analogy of activated macrophages: the proinflammatory "classical" activation phenotype (M1) and the anti-inflammatory "alternative" activated phenotype (M2). However, this simplistic view of microglial phenotypes does not adequately reflect the complex physiology of microglia.

The progression of neurodegenerative disease induces the loss of microglial homeostatic molecules and functions, leading to chronically progressive neuroinflammation. In addition, recent studies demonstrated that a common disease-associated microglia (DAM) or "neurodegenerative" phenotype, defined by a small set of upregulated genes, was observed in neurodegenerative diseases including AD, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia, and aging. However, it remains unclear whether the loss of homeostatic function in microglia or the DAM phenotype is correlated with the degree of neuronal cell loss, and whether DAM is beneficial or detrimental to neurodegenerative diseases.

In this study, we performed RNA sequencing of microglia isolated from three representative neurodegenerative mouse models, AppNL-G-F/NL-G-F with amyloid pathology, rTg4510 with tauopathy, and SOD1G93A with motor neuron disease. In parallel, gene expression patterns of the human precuneus with early Alzheimer's change (n = 11) and control brain (n = 14) were also analyzed by RNA sequencing.

We found that a substantial reduction of homeostatic microglial genes in rTg4510 and SOD1G93A microglia, whereas DAM genes were uniformly upregulated in all mouse models. The reduction of homeostatic microglial genes was correlated with the degree of neuronal cell loss. In human precuneus with early AD pathology, reduced expression of genes related to microglia- and oligodendrocyte-specific markers was observed, although the expression of DAM genes was not upregulated. Our results implicate a loss of homeostatic microglial function in the progression of AD and other neurodegenerative diseases. Moreover, analyses of human precuneus also suggest loss of microglia and oligodendrocyte functions induced by early amyloid pathology in human.

View the full article at FightAging

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