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Microglial metabolism is a pivotal factor in sexual dimorphism in Alzheimer's disease.

ABSTRACT: Age and sex are major risk factors in Alzheimer's disease (AD) with a higher incidence of the disease in females. Neuroinflammation, which is a hallmark of AD, contributes to disease pathogenesis and is inexorably linked with inappropriate microglial activation and neurodegeneration. We investigated sex-related differences in microglia in APP/PS1 mice and in post-mortem tissue from AD patients. Changes in genes that are indicative of microglial activation were preferentially increased in cells from female APP/PS1 mice and cells from males and females were morphological, metabolically and functionally distinct. Microglia from female APP/PS1 mice were glycolytic and less phagocytic and associated with increased amyloidosis whereas microglia from males were amoeboid and this was also the case in post-mortem tissue from male AD patients, where plaque load was reduced. We propose that the sex-related differences in microglia are likely to explain, at least in part, the sexual dimorphism in AD.

SUBMITTER: Guillot-Sestier MV

PROVIDER: S-EPMC8192523 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Microglial metabolism is a pivotal factor in sexual dimorphism in Alzheimer's disease.

Guillot-Sestier Marie-Victoire MV Araiz Ana Rubio AR Mela Virginia V Gaban Aline Sayd AS O'Neill Eoin E Joshi Lisha L Chouchani Edward T ET Mills Evanna L EL Lynch Marina A MA

Communications biology 20210610 1

Age and sex are major risk factors in Alzheimer's disease (AD) with a higher incidence of the disease in females. Neuroinflammation, which is a hallmark of AD, contributes to disease pathogenesis and is inexorably linked with inappropriate microglial activation and neurodegeneration. We investigated sex-related differences in microglia in APP/PS1 mice and in post-mortem tissue from AD patients. Changes in genes that are indicative of microglial activation were preferentially increased in cells f ...[more]

PMID: 34112929

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Project description:BackgroundTau hyper-phosphorylation has been considered a major contributor to neurodegeneration in Alzheimer's disease (AD) and related tauopathies, and has gained prominence in therapeutic development for AD. To elucidate the pathogenic mechanisms underlying AD and evaluate therapeutic approaches targeting tau, numerous transgenic mouse models that recapitulate critical AD-like pathology have been developed. Tau P301S transgenic mice is one of the most widely used mouse models in AD research. Extensive studies have demonstrated that sex significantly influences AD pathology, behavioral status, and therapeutic outcomes, suggesting that studies using mouse models of AD must consider sex- and age-related differences in neuropathology, behavior, and plasma content.MethodWe systematically investigated differences in tau P301S transgenic mice (PS19 line) and wildtype littermates of different sex behavioral performance, tau neuropathology, and biomarkers in plasma and brain.ResultsMale P301S transgenic mice exhibited significant changes in weight loss, survival rate, clasping, kyphosis, composite phenotype assessment, nest building performance, tau phosphorylation at Ser202/Thr205, and astrocyte activation compared to that of wild-type littermates. In contrast, female P301S transgenic mice were only sensitive in the Morris water maze and open field test. In addition, we characterized the absence of macrophage-inflammatory protein (MIP-3α) and the upregulation of interferon (IFN)-γ, interleukin (IL)-5, and IL-6 in the plasma of P301S transgenic mice, which can be served as potential plasma biomarkers in P301S Tg mice. Male P301S transgenic mice expressed more monokine induced by IFN-γ (MIG), tumor necrosis factor-α (TNF-α), IL-10, and IL-13 than those of female P301S mice.ConclusionOur findings highlight sexual dimorphism in the behavior, neuropathology, and plasma proteins in tau P301S transgenic AD mice, indicating that the use of male P301S transgenic mice may be more suitable for assessing anti-phosphorylated tau therapeutic strategies for AD and related tauopathies, and the MIP-3α may be a new potential plasma biomarker.

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Microglial metabolism is a pivotal factor in sexual dimorphism in Alzheimer's disease.

Publications

Microglial metabolism is a pivotal factor in sexual dimorphism in Alzheimer's disease.

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