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Microglia protect against age-associated brain pathologies

ABSTRACT: Microglia are brain-resident macrophages that contribute to central nervous system development, maturation, and preservation. Here, we examine the consequences of lifelong absence of microglia on ageing using the Csf1rΔFIRE/ΔFIRE mouse model. In juvenile Csf1rΔFIRE/ΔFIRE mice, we show that microglia are largely dispensable for the transcriptomic maturation of other brain cell types. In contrast, with advancing age, multiple pathologies accumulate in Csf1rΔFIRE/ΔFIRE brains, astrocytes and oligodendrocyte-lineage cells become increasingly dysregulated, and white matter integrity declines, mimicking many of the pathological features of human CSF1R-related leukoencephalopathy. The thalamus is particularly sensitive to neuropathological changes in the absence of microglia, with atrophy, neuron loss, vascular disturbances, macroglial dysregulation, and severe calcifications all detected in this region. Thalamic calcification formation, which often occurs with normal ageing, is dramatically accelerated in Csf1rΔFIRE/ΔFIRE brains but can be prevented via transplantation of wild-type microglia. Our results indicate that lifelong absence of microglia results in an age-related neurodegenerative condition that can be prevented by the transplantation of healthy microglia.

ORGANISM(S): Mus musculus

PROVIDER: GSE267545 | GEO | 2024/05/22

REPOSITORIES: GEO

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Project description:BACKGROUND: The gut-brain axis and the intestinal microbiota are emerging as key players in health and disease. Shifts in intestinal microbiota composition affect a variety of systems, however, evidence of their direct impact on cognitive functions is still lacking. We tested whether faecal microbiota transplant (FMT) from aged donor mice into young adult recipients affected the hippocampus, an area of the central nervous system (CNS) known to be affected by the ageing process, and related functions.METHODS AND FINDINGS: Young adult mice were transplanted with the microbiota from either aged or age-matched donor mice. Following transplantation, characterization of the microbiotas and metabolomics profiles along with a battery of cognitive and behavioural tests were performed. Label-free quantitative proteomics was employed to monitor protein expression in the hippocampus of the recipients. Gut permeability, levels of circulating cytokines and expression of markers of microglia cells were also assessed. FMT from aged donors led to impaired spatial learning and memory in young adult recipients, whereas anxiety, explorative behaviour and locomotor activity remained unaffected. This was paralleled by altered expression of proteins involved in synaptic plasticity and neurotransmission in the hippocampus. Also, a strong reduction of bacteria associated with short-chain fatty acids (SCFAs) production (Lachnospiraceae, Faecalibaculum and Ruminococcaceae) and disorders of the CNS (Prevotellaceae and Ruminococcaceae) was observed. Finally, microglia cells of the hippocampus fimbria, acquired an ageing-like phenotype, while gut permeability and levels of circulating cytokines remained unaffected.CONCLUSIONS: These results demonstrate a direct effect of the age-associated shifts of the microbiota on protein expression and key functions of the central nervous system. Furthermore, these results additionally highlight the paramount importance of the gut-brain axis in ageing and provide a strong rationale to devise therapies aiming to restore a young-like microbiota to improve cognitive functions in the elderly.