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Brain hypothyroidism leads to immune tolerance in microglia in Alzheimer's disease

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE219131 | GEO | 2023/09/01

REPOSITORIES: GEO

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Brain hypothyroidism leads to immune tolerance in microglia in Alzheimer's disease [scRNA-seq]

Project description:An imbalance in thyroid hormones (THs) is associated with reversible dementia and Alzheimer’s disease (AD) pathogenesis. Whether hypothyroidism occurs in AD brains and how it affects AD pathology remain largely unknown. Here, we find that reduced conversion of thyroxine (T4) to tri-iodothyronine (T3) in the brain by decreased iodothyronine deiodinase 2 (DIO2) leads to hippocampal hypothyroidism in early AD model mice prior to TH changes in the blood. A TH deficiency causes immune tolerance with decreased phagocytic activity in microglia, thereby aggravating AD pathology. We demonstrate that microglial ecto-5’-nucleotidase (CD73) is reduced in the hypothyroid state and that its inhibition contributes to immune tolerance in microglia. Thus, our data define a molecular mechanism through which decreased conversion of T4 to T3 in the early AD brain, and consequent brain hypothyroidism causes microglial dysfunction and exacerbates AD pathology.

2023-09-01 | GSE219130 | GEO

Brain hypothyroidism leads to immune tolerance in microglia in Alzheimer's disease [RNA-seq]

2023-09-01 | GSE219129 | GEO

SEX-DEPENDENT APOE4 NEUTROPHIL-MICROGLIA INTERACTIONS DRIVE COGNITIVE IMPAIRMENT IN ALZHEIMER'S DISEASE

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Multi-transcriptomics reveals brain cellular responses to peripheral infection in Alzheimer's disease model mice

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Microglia, Alzheimer's disease, and complement.

Project description:Microglia, the immune cell of the brain, are implicated in cascades leading to neuronal loss and cognitive decline in Alzheimer's disease (AD). Recent genome-wide association studies have indicated a number of risk factors for the development of late-onset AD. Two of these risk factors are an altered immune response and polymorphisms in complement receptor 1. In view of these findings, we discuss how complement signalling in the AD brain and microglial responses in AD intersect. Dysregulation of the complement cascade, either by changes in receptor expression, enhanced activation of different complement pathways or imbalances between complement factor production and complement cascade inhibitors may all contribute to the involvement of complement in AD. Altered complement signalling may reduce the ability of microglia to phagocytose apoptotic cells and clear amyloid beta peptides, modulate the expression by microglia of complement components and receptors, promote complement factor production by plaque-associated cytokines derived from activated microglia and astrocytes, and disrupt complement inhibitor production. The evidence presented here indicates that microglia in AD are influenced by complement factors to adopt protective or harmful phenotypes and the challenge ahead lies in understanding how this can be manipulated to therapeutic advantage to treat late onset AD.

| S-EPMC3432348 | biostudies-other

Microglia in Alzheimer's disease.

Project description:Proliferation and activation of microglia in the brain, concentrated around amyloid plaques, is a prominent feature of Alzheimer's disease (AD). Human genetics data point to a key role for microglia in the pathogenesis of AD. The majority of risk genes for AD are highly expressed (and many are selectively expressed) by microglia in the brain. There is mounting evidence that microglia protect against the incidence of AD, as impaired microglial activities and altered microglial responses to ?-amyloid are associated with increased AD risk. On the other hand, there is also abundant evidence that activated microglia can be harmful to neurons. Microglia can mediate synapse loss by engulfment of synapses, likely via a complement-dependent mechanism; they can also exacerbate tau pathology and secrete inflammatory factors that can injure neurons directly or via activation of neurotoxic astrocytes. Gene expression profiles indicate multiple states of microglial activation in neurodegenerative disease settings, which might explain the disparate roles of microglia in the development and progression of AD pathology.

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Microglia coordinate the anti-tumor immune response to breast cancer brain metastasis

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-09-01 | GSE147949 | GEO