Brain hypothyroidism leads to immune tolerance in microglia in Alzheimer's disease [RNA-seq]
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PROVIDER: PRJNA907147 | ENA |
REPOSITORIES: ENA
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Project description:Brain hypothyroidism leads to immune tolerance in microglia in Alzheimer's disease
| PRJNA907141 | ENA
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
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 | GSE219129 | GEO
Project description:Brain hypothyroidism leads to immune tolerance in microglia in Alzheimer's disease [scRNA-seq]
| PRJNA907148 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-09-01 | GSE219131 | GEO
Project description:Isolation of glia from Alzheimer's mice reveals inflammation and dysfunction. Reactive astrocytes and microglia are associated with amyloid plaques in Alzheimer's disease (AD). Yet, not much is known about the molecular alterations underlying this reactive phenotype. To get an insight into the molecular changes underlying AD induced astrocyte and microglia reactivity, we performed a transcriptional analysis on acutely isolated astrocytes and microglia from the cortex of aged controls and APPswe/PS1dE9 AD mice. As expected, both cell types acquired a proinflammatory phenotype, which confirms the validity of our approach. Interestingly, we observed that the immune alteration in astrocytes was relatively more pronounced than in microglia. Concurrently, our data reveal that astrocytes display a reduced expression of neuronal support genes and genes involved in neuronal communication. The microglia showed a reduced expression of phagocytosis and/or endocytosis genes. Co-expression analysis of a human AD expression data set and the astrocyte and microglia data sets revealed that the inflammatory changes in astrocytes were remarkably comparable in mouse and human AD, whereas the microglia changes showed less similarity. Based on these findings we argue that chronically proinflammatory astrocyte and microglia phenotypes, showing a reduction of genes involved in neuronal support and neuronal signaling, are likely to contribute to the neuronal dysfunction and cognitive decline in AD. 2 cell types from 2 conditions: cortical microglia and cortical astrocytes from 15-18 month old APPswe/PS1dE9 mice compared to wildtype littermates. Biological replicates: microglia from APPswe/PS1dE9, N=7, microglia from WT, N=7, astrocytes from APPswe/PS1dE9, N=4, microglia from WT, N=4
2015-11-04 | E-GEOD-74615 | biostudies-arrayexpress
Project description:We examined the role of TREM2 on microglia responses to amyloid-beta deposition in a mouse model of Alzheimer's disease Microglia were FACS-purified from 8.5 month old WT, Trem2-/-, 5XFAD, and Trem2-/- 5XFAD mice
2015-03-13 | E-GEOD-65067 | biostudies-arrayexpress
Project description:Neuroimmunity is present as an important mechanism in the brains of Alzheimer's patients, and microglia are a key component of the brain's innate immune response during the development and progression of Alzheimer's disease. The interferon pathway plays an important role in the pathophysiologic mechanisms of AD. RNA-seq was performed on LPS-treated microglia(LPS) and untreated microglia(WT) to further explore.
2024-03-11 | GSE261007 | GEO
Project description:GFAP and vimentin deficiency alters gene expression in astrocytes and microglia in wild-type mice and changes the transcriptional response of reactive glia in mouse model for Alzheimer's disease. Reactive astrocytes with an increased expression of intermediate filament (IF) proteins Glial Fibrillary Acidic Protein (GFAP) and Vimentin (VIM) surround amyloid plaques in Alzheimer's disease (AD). The functional consequences of this upregulation are unclear. To identify molecular pathways coupled to IF regulation in reactive astrocytes, and to study the interaction with microglia, we examined WT and APPswe/PS1dE9 (AD) mice lacking either GFAP, or both VIM and GFAP, and determined the transcriptome of cortical astrocytes and microglia from 15- to 18-month-old mice. Genes involved in lysosomal degradation (including several cathepsins) and in inflammatory response (including Cxcl5, Tlr6, Tnf, Il1b) exhibited a higher AD-induced increase when GFAP, or VIM and GFAP, were absent. The expression of Aqp4 and Gja1 displayed the same pattern. The downregulation of neuronal support genes in astrocytes from AD mice was absent in GFAP/VIM null mice. In contrast, the absence of IFs did not affect the transcriptional alterations induced by AD in microglia, nor was the cortical plaque load altered. Visualizing astrocyte morphology in GFAP-eGFP mice showed no clear structural differences in GFAP/VIM null mice, but did show diminished interaction of astrocyte processes with plaques. Microglial proliferation increased similarly in all AD groups. In conclusion, absence of GFAP, or both GFAP and VIM, alters AD-induced changes in gene expression profile of astrocytes, showing a compensation of the decrease of neuronal support genes and a trend for a slightly higher inflammatory expression profile. However, this has no consequences for the development of plaque load, microglial proliferation, or microglial activation. 2 cell types from 6 conditions: cortical microglia and cortical astrocytes from 15-18 month old APPswe/PS1dE9 mice compared to wildtype littermates. Biological replicates: microglia from APPswe/PS1dE9, N=7, microglia from WT, N=7, astrocytes from APPswe/PS1dE9, N=4, microglia from WT, N=4
2015-11-04 | E-GEOD-74614 | biostudies-arrayexpress
Project description:Sugar utilization by microglia in Alzheimer's disease
| PRJNA961771 | ENA