Editors' ChoiceNeurodegeneration

Microglial sex affects Alzheimer’s disease

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Science Translational Medicine  08 Jan 2020:
Vol. 12, Issue 525, eaba2905
DOI: 10.1126/scitranslmed.aba2905

Abstract

Sex-specific microglial microRNAs impact tau pathogenesis.

How female and male brains develop and diverge is an intense area of research, and how much the brain’s function can be attributed to biology versus social experience is a challenging question to answer. What is undeniable is that sex differences have heterogeneous effects on even the normal human brain. Past studies have shown that there are anatomical differences between male and female brains, including the volume and distribution of specific features, such as gray and white matter. Only recently have these sex differences gained traction in the pathogenesis and presentation of neurological diseases, although these studies have mostly been on a larger imaging and gross anatomical basis. Yet, despite the prevalence of sex differences, there remains a paucity of studies examining sex and gender differences on a cellular and molecular level in neurodegeneration. Specifically, in Alzheimer’s disease (AD), numerous studies have looked at the tau pathology and molecular mechanisms involved in neuronal degeneration. Previous studies have implicated certain cell types within the brain’s microenvironment in the spread of AD pathology, including microglia, which are the major inflammatory cells and respond to pathogenesis by phagocytosing and removing damaged cells. However, whether microglia in males and females respond to tau pathology differently remains to be further elucidated.

Now Kodama et al. show that there are sex-related differences in microRNAs (miRNAs) expressed in microglia that lead to sex-specific changes in the transcriptome and tau pathology. Using mouse models of tauopathy, the researchers found microglial sex differences in a total of 927 mRNA transcripts, with 436 genes up-regulated and 491 genes down-regulated. Some of the pathways involved in neurodegeneration associated with these microglial sex differences included tumor necrosis factor–α signaling, KRAS signaling, hypoxia, P53 pathway, and inflammatory response. They further showed that 61 miRNAs were differentially expressed in the microglial cells of male and female mice. Loss of microglial miRNAs resulted in the enrichment of genes involved in inflammation and phagocytosis, including Spp1, Ccl6, Lpl, Il1b, and Cst7, characteristic of disease-associated microglia and tau pathology in male mice.

Although these findings indicate that a subset of microglial miRNAs are key contributors to sex-specific microglial phenotypes in the context of neurodegenerative diseases, they also raise several biological questions. Additional microenvironment studies need to be conducted to determine whether these microglial miRNA sex differences are seen in other neurodegenerative diseases, such as Huntington’s or Parkinson’s disease, and whether they result in differential onset of tau pathology and clearance.

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