Exploring Sex-Related Differences in Microglia May Be a Game-Changer in Precision Medicine

Lynch, Marina A.

doi:10.3389/fnagi.2022.868448

Cited by 73 publications

(51 citation statements)

References 177 publications

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“…For example, microglia from female mice exhibit augmented expression of an APOE-driven network of genes associated with aging, amyloidosis, and tau [30][31][32]. Yet, whilst peripheral human immune cells isolated from men and women show phenotypic and functional variations [1,2], there are only limited studies examining sex differences in human microglia [33][34][35].…”

Section: Introductionmentioning

confidence: 99%

Alzheimer’s disease-related transcriptional sex differences in myeloid cells

Coales

Tsartsalis

Fancy

et al. 2022

J Neuroinflammation

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Sex differences have been identified in many diseases associated with dysregulated immune responses, including Alzheimer’s disease (AD), for which approximately two-thirds of patients are women. An accumulating body of research indicates that microglia may play a causal role in the pathogenesis of this disease. We hypothesised that sex differences in the transcriptome of human myeloid cells may contribute to the sex difference observed in AD prevalence. To explore this, we assessed bulk and single-nuclear RNA sequencing data sets generated from four human derived myeloid cell populations: post-mortem microglial nuclei, peripheral monocytes, monocyte-derived macrophages (MDMs) and induced pluripotent stem cell derived microglial-like cells (MGLs). We found that expression of AD risk genes, gene signatures associated with the inflammatory response in AD, and genes related to proinflammatory immune responses were enriched in microglial nuclei isolated from aged female donors without ante-mortem neurological disease, relative to those from males. In addition, these inflammation-associated gene sets were found to be enriched in peripheral monocytes isolated from postmenopausal women and in MDMs obtained from premenopausal individuals relative to age-matched males. Expression of these gene sets did not differ in MDMs derived from women whose blood was sampled across the menstrual cycle or in MGLs cultured with 17β-oestradiol. This suggests that the observed gene set enrichments in myeloid cells from women were not being driven by acute hormonal influences. Together, these data support the hypothesis that the increased prevalence of AD in women may be partly explained by a myeloid cell phenotype biased towards expression of biological processes relevant to AD.

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Section: Introductionmentioning

confidence: 99%

Alzheimer’s disease-related transcriptional sex differences in myeloid cells

Coales

Tsartsalis

Fancy

et al. 2022

J Neuroinflammation

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“…It could be interesting to extend our work to females, as sex-related differences have been well documented in (neuro)inflammatory responses, including in intrinsic properties of microglial cells. 49…”

Section: Discussionmentioning

confidence: 99%

Persistent neuroinflammation and behavioural deficits after single mild traumatic brain injury

Drieu

Lanquetin

Prunotto

et al. 2022

J Cereb Blood Flow Metab

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Despite an apparently silent imaging, some patients with mild traumatic brain injury (TBI) experience cognitive dysfunctions, which may persist chronically. Brain changes responsible for these dysfunctions are unclear and commonly overlooked. It is thus crucial to increase our understanding of the mechanisms linking the initial event to the functional deficits, and to provide objective evidence of brain tissue alterations underpinning these deficits. We first set up a murine model of closed-head controlled cortical impact, which provoked persistent cognitive and sensorimotor deficits, despite no evidence of brain contusion or bleeding on MRI, thus recapitulating features of mild TBI. Molecular MRI for P-selectin, a key adhesion molecule, detected no sign of cerebrovascular inflammation after mild TBI, as confirmed by immunostainings. By contrast, in vivo PET imaging with the TSPO ligand [18F]DPA-714 demonstrated persisting signs of neuroinflammation in the ipsilateral cortex and hippocampus after mild TBI. Interestingly, immunohistochemical analyses confirmed these spatio-temporal profiles, showing a robust parenchymal astrogliosis and microgliosis, at least up to 3 weeks post-injury in both the cortex and hippocampus. In conclusion, we show that even one single mild TBI induces long-term behavioural deficits, associated with a persistent neuro-inflammatory status that can be detected by PET imaging.

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“…Why sex-related differences in microglial phenotype exist in AD and APP/PS1 mice remains unclear but factors that are likely contributors include sex hormones, microRNA, chromosomal make-up and blood brain barrier permeability ( Weber and Clyne, 2021 ; Lynch, 2022 ). For instance, neuromodulatory effects of estrogens have been described ( Acosta-Martinez, 2020 ) and microRNAs, which also modulate immune networks, ( Kodama et al, 2020 ) exhibit sex-related differences.…”

Section: Discussionmentioning

confidence: 99%

Sex-Related Microglial Perturbation Is Related to Mitochondrial Changes in a Model of Alzheimer’s Disease

O’Neill

Mela

Gaban

et al. 2022

Front. Cell. Neurosci.

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Many studies implicate microglia in the pathogenesis of Alzheimer’s disease (AD) but precisely how these cells make their impact has not been determined to date. One contributory factor is likely to be the enhanced production of inflammatory mediators and it is now known that microglia with this secretory phenotype exhibit other adaptations including in their morphology, function, and metabolism. AD, like many neurological disorders, demonstrates a sex bias and recent evidence indicates that the sexual dimorphism in microglial function, which has been recognized for many years in early development, persists into adulthood and aging. Here, we demonstrate sex-related differences in microglia from post mortem tissue of male and female AD patients and a marked increase in the number of dystrophic and rod-shaped microglia in tissue from female AD patients compared with males. Furthermore, there was an increase in iron-laden microglia in tissue from female AD patients and this has been reported to reflect mitochondrial changes. To address this further, we assessed changes in microglia from male and female APP/PS1 mice and demonstrate that iron accumulation in microglia is increased to a greater extent in tissue prepared from females compared with males. This was associated with altered expression of genes coding for proteins that modulate mitochondrial function. The findings suggest that sex-related differences in the severity and perhaps incidence of AD may, at least in part, arise from sexual dimorphism in microglia.

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Exploring Sex-Related Differences in Microglia May Be a Game-Changer in Precision Medicine

Cited by 73 publications

References 177 publications

Alzheimer’s disease-related transcriptional sex differences in myeloid cells

Alzheimer’s disease-related transcriptional sex differences in myeloid cells

Persistent neuroinflammation and behavioural deficits after single mild traumatic brain injury

Sex-Related Microglial Perturbation Is Related to Mitochondrial Changes in a Model of Alzheimer’s Disease

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