Expression data from microglia in Abeta and TAU mouse models of Alzheimer Disease
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PROVIDER: PRJNA530765 | ENA |
REPOSITORIES: ENA
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Project description:Microglia activation is a hallmark in Alzheimer Disease. Non-active and Active microglia were isolated from young and aged WT mice and before- and after- pathology mouse models of Alzheimer Disease. Microarray analysis was used to determine the global gene expression programe in microglia during pathological (Abeta or TAU pathology) versus control state.
2021-03-03 | GSE129296 | GEO
Project description:Alzheimer’s disease (AD) is the most prevalent form of dementia and is characterized by abnormal extracellular aggregates of amyloid-b and intraneuronal hyperphosphorylated, tau tangles and neuropil threads. Microglia, the tissue-resident macrophages of the central nervous system (CNS), are important for CNS homeostasis and implicated in AD pathology. In amyloid mouse models, a phagocytic/activated microglia phenotype has been identified. How increasing levels of amyloid-b and tau pathology affect human microglia transcriptional profiles is unknown. Here, we performed snRNAseq on 482,472 nuclei from non-demented control brains and AD brains containing only amyloid-b plaques or both amyloid-b plaques and tau pathology. Within the microglia population, distinct expression profiles were identified of which two were AD pathology-associated. The phagocytic/activated AD1-microglia population abundance strongly correlated with tissue amyloid-b load and localized to amyloid-b plaques. The AD2-microglia abundance strongly correlated with tissue phospho-tau load and these microglia were more abundant in samples with over tau pathology. This full characterization of human disease associated microglia phenotypes provides new insights in the pathophysiological role of microglia in AD and offers new targets for microglia-state-specific therapeutic strategies.
2021-02-20 | GSE148822 | GEO
Project description:Polygenic risk scores have identified that genetic variants without genome-wide significance still add to the genetic risk of developing Alzheimer’s disease (AD). Whether and how subthreshold risk loci translate into relevant disease pathways, is unknown. We investigate here the involvement of AD risk variants in the transcriptional responses of two mouse models: APPswe/PS1L166P and Thy-TAU22. A unique gene expression module, highly enriched for AD risk genes, is specifically responsive to Aβ but not TAU pathology. We identify in this module 7 established AD risk genes (APOE, CLU, INPP5D, CD33, PLCG2, SPI1 and FCER1G) and 11 AD GWAS genes below the genome-wide significance threshold (GPC2, TREML2, SYK, GRN, SLC2A5, SAMSN1, PYDC1, HEXB, RRBP1, LYN and BLNK), that become significantly upregulated when exposed to Aβ. Single microglia sequencing confirms that Aβ, not TAU, pathology induces marked transcriptional changes in microglia, including increased proportions of activated microglia. We conclude that genetic risk of AD functionally translates into different microglia pathway responses to Aβ pathology, placing AD genetic risk downstream of the amyloid pathway but upstream of TAU pathology.
2020-01-14 | GSE110741 | GEO
Project description:Polygenic risk scores have identified that genetic variants without genome-wide significance still add to the genetic risk of developing Alzheimer’s disease (AD). Whether and how subthreshold risk loci translate into relevant disease pathways, is unknown. We investigate here the involvement of AD risk variants in the transcriptional responses of two mouse models: APPswe/PS1L166P and Thy-TAU22. A unique gene expression module, highly enriched for AD risk genes, is specifically responsive to Aβ but not TAU pathology. We identify in this module 7 established AD risk genes (APOE, CLU, INPP5D, CD33, PLCG2, SPI1 and FCER1G) and 11 AD GWAS genes below the genome-wide significance threshold (GPC2, TREML2, SYK, GRN, SLC2A5, SAMSN1, PYDC1, HEXB, RRBP1, LYN and BLNK), that become significantly upregulated when exposed to Aβ. Single microglia sequencing confirms that Aβ, not TAU, pathology induces marked transcriptional changes in microglia, including increased proportions of activated microglia. We conclude that genetic risk of AD functionally translates into different microglia pathway responses to Aβ pathology, placing AD genetic risk downstream of the amyloid pathway but upstream of TAU pathology.
2020-01-14 | GSE142267 | GEO
Project description:Proteopathic seeds are soluble species of aggregation prone molecules such as tau, that are competent to instruct endogenous proteins to undergo templated misfolding. Yet the idea of proteopathic seeds for tau is largely abstract, and the relationship of the seeds to the final fibrils that define the diseases has not been determined. We utilized mass spectrometry (MS), and in vitro bioassays to characterize the soluble tau species, derived from human Alzheimer brain, that are capable of inducing tau seeding in bioreporter cells and in vivo. Multiple post translational modifications (PTM) were identified by MS, including phosphorylations, acetylations, and ubiquitinations. While the patterns are quite similar to that of post translational modifications on insoluble paired helical filament preparations, the presence of fewer overall post translational modifications, and some unique modifications, distinguish soluble seed competent tau from filamentous tau in Alzheimer disease. Surprisingly, the presence of ubiquitin modifications on the soluble seed competent species correlates positively with bioactivity, and the stoichiometry of ubiquitin occupancy and other PTMs¬ correlate with the aggressiveness of clinical disease measured by age of onset and rapidity of progression. These results define the bioactive, seed competent tau species as being closely related to, but distinct from, mature paired helical filaments, and provide insight into the molecular features of tau PTMs that ultimately generate the bioactive conformation of tau present in Alzheimer disease (AD).
2025-05-06 | PXD032192 | Pride
Project description:Alzheimer’s disease (AD) is the most prevalent neurodegenerativedisorder. Currently, anti-amyloid antibody treatments modestly slow disease progression in milddementia due to AD.Emerging evidence shows that homeostatic dysregulation of the brainimmune system, especially that orchestrated by microglia, plays a significant role in the onset andprogression of the disease, including an increase in neuroinflammation and oxidative stress.Thus,a major question is how to modulate the phenotype and function of microglia to treat AD.Xenongas (Xe) is a noble gas used in human patients as an anesthetic and neuroprotectant in treatingbrain injuries. Xe penetratestheblood-brain barrier, which can make it an effective therapeutic.WeidentifiedthatXeinhalationpolarizesmouse and human microglia towards an intermediatestate of activation that we have termedas‘pre-MGnD’ in anacute neurodegeneration model andmouse models with AD-like pathology, i.e.,5xFAD (amyloid) and P301S (tau). This microglialphenotypic transition enhanced amyloid plaque compaction and reduced dystrophic neurites.Moreover, Xe inhalation reduced brain atrophy neuroinflammationand improved nest-buildingbehavior in APOE4:P301S mice. Mechanistically, Xe inhalation polarizes homeostatic microgliatoward a pre-MGnD state via IFNsignaling that maintains the microglial phagocytic responsewhile suppressing its pro-inflammatory properties. These resultssupport the translation of Xeinhalation as a novel approach to treatingAD.
2025-01-15 | GSE275386 | GEO
Project description:Proteopathic seeds are soluble species of aggregation prone molecules such as tau, that are competent to instruct endogenous proteins to undergo templated misfolding. Yet the idea of proteopathic seeds for tau is largely abstract, and the relationship of the seeds to the final fibrils that define the diseases has not been determined. We utilized mass spectrometry (MS), and in vitro bioassays to characterize the soluble tau species, derived from human Alzheimer brain, that are capable of inducing tau seeding in bioreporter cells and in vivo. Multiple post translational modifications (PTM) were identified by MS, including phosphorylations, acetylations, and ubiquitinations. While the patterns are quite similar to that of post translational modifications on insoluble paired helical filament preparations, the presence of fewer overall post translational modifications, and some unique modifications, distinguish soluble seed competent tau from filamentous tau in Alzheimer disease. Surprisingly, the presence of ubiquitin modifications on the soluble seed competent species correlates positively with bioactivity, and the stoichiometry of ubiquitin occupancy and other PTMs¬ correlate with the aggressiveness of clinical disease measured by age of onset and rapidity of progression. These results define the bioactive, seed competent tau species as being closely related to, but distinct from, mature paired helical filaments, and provide insight into the molecular features of tau PTMs that ultimately generate the bioactive conformation of tau present in Alzheimer disease (AD).
2025-05-06 | PXD036692 | Pride
Project description:Novel Alzheimer risk genes determine the microglia response to amyloid-β but not to TAU pathology
| PRJNA596464 | ENA
Project description:Novel Alzheimer risk genes determine the microglia response to amyloid-β but not to TAU pathology
| PRJNA434454 | ENA
Project description:Inhaled Xenon modulates microglia and ameliorates disease in mouse models of amyloidosis and tauopathy [Tau]
| PRJNA1150582 | ENA