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Microglia contribute to the propagation of Abeta pathology into healthy brain tissue

ABSTRACT: Microglia contribute to the propagation of Abeta pathology into healthy brain tissue

PROVIDER: PRJNA683823 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13225500.fastq.gz	Fastqsanger.gz
	SRR13225487.fastq.gz	Fastqsanger.gz
	SRR13225488.fastq.gz	Fastqsanger.gz
	SRR13225489.fastq.gz	Fastqsanger.gz
	SRR13225490.fastq.gz	Fastqsanger.gz

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Microglia contribute to the propagation of Abeta pathology into healthy brain tissue

Project description:The extracellular accumulation of amyloid-beta (A) peptides is a major hallmark of Alzheimer’s disease (AD). It is widely accepted that microglia associate with A plaques and appear morphologically activated especially in their immediate vicinity. Whether microglia play a role in A plaque formation and contribute to the propagation of A pathology remains however unknown. We therefore investigated the characteristics of microglia during neural transplantation experiments where wild-type neurons are grafted into the cortex of AD mouse models. Here, we demonstrate that A from the transgenic host tissue is able to enter and deposit within wild-type (WT) grafts, a process that is accompanied by massive microglia infiltration. Notably, manipulation of microglia function or microglia elimination significantly reduced A deposition within the grafts. Similarly, time-lapse in vivo two-photon imaging revealed that microglia transport A to the site of injury thereby identifying microglia as cellular carrier of A that propagate A pathology in previously unaffected CNS tissue. Our data thus argue for a hitherto unexplored mechanism of A propagation.

2022-01-27 | GSE162920 | GEO

Expression data from microglia in Abeta and TAU mouse models of Alzheimer Disease

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

Osteopontin-producing microglia contribute to Alzheimer’s disease (AD) pathology and severity

Project description:We define a pathogenic subset of microglia that is distinguished by expression of the CD11c protein and by production of osteopontin (OPN). OPN production by this CD11c+ microglial subset correlates positively with disease pathology and severity in the 5XFAD mouse model and in AD patients. Genetic ablation of OPN in 5XFAD mice leads to reduced development of pro-inflammatory CD11c+ microglia, increased amyloid beta (Aβ) phagocytosis and improved cognitive function.

2023-02-01 | GSE191118 | GEO

CSF1R inhibition rescues tau pathology and neurodegeneration in an A/T/N model with combined AD pathologies, while preserving plaque associated microglia

Project description:Alzheimer's disease (AD) is characterized by a sequential progression of amyloid plaques (A), neurofibrillary tangles (T) and neurodegeneration (N), constituting ATN pathology. While microglia are considered key contributors to AD pathogenesis, their contribution in the combined presence of ATN pathologies remains incompletely understood. As sensors of the brain microenvironment, microglial phenotypes and contributions are importantly defined by the pathologies in the brain, indicating the need for their analysis in preclinical models that recapitulate combined ATN pathologies, besides their role in A and T models only. Here, we report a new tau-seed model in which amyloid pathology facilitates bilateral tau propagation associated with brain atrophy, thereby recapitulating robust ATN pathology. Single-cell RNA sequencing revealed that ATN pathology exacerbated microglial activation towards disease-associated microglia (DAM) states, with a significant upregulation of Apoe as compared to amyloid-only models (A). Importantly, Colony-Stimulating Factor 1 Receptor inhibition preferentially eliminated non-plaque-associated versus plaque associated microglia. The preferential depletion of non-plaque-associated microglia significantly attenuated tau pathology and neuronal atrophy, indicating their detrimental role during ATN progression. Together, our data reveal the intricacies of microglial activation and their contributions to pathology in a model that recapitulates the combined ATN pathologies of Alzheimer's disease. Our data may provide a basis for microglia-targeting therapies selectively targeting detrimental microglial populations, while conserving protective populations.

2021-06-03 | GSE176032 | GEO

Contribution of Age, Brain Region, Mood Disorder Pathology, and Interindividual Factors on the Methylome of Human Microglia

Project description:Total of 56 microglia samples from postmortem brain tissue of four different brain regions, medial frontal gyrus (MFG), superior temporal gyrus (STG), subventricular zone (SVZ) and thalamus (THA), of 22 donors, encompassing 1 patient with schizophrenia, 13 patients with mood disorder pathology, and 8 control subjects, were isolated and assayed using a genome-wide methylation array to characterize the DNA methylation landscape of human microglia and the factors that contribute to variations in the microglia methylome

2022-01-31 | GSE191200 | GEO

Xenografted human microglia display diverse transcriptomic states in response to Alzheimer’s disease-related Aβ pathology

Project description:Microglia are central players in Alzheimer’s Disease (AD) pathology, but analyzing microglia states in human brain samples is challenging due to genetic diversity, postmortem delay and admixture of pathologies. To circumvent these issues, here we generated 138,577 single cell expression profiles of human stem cell-derived microglia xenotransplanted in the brain of the AppNL-G-F model of amyloid pathology and wild type controls. Xenografted human microglia adopt a disease-associated (DAM) profile similar to that seen in mouse microglia, but display a more pronounced HLA state, likely related to antigen presentation in response to amyloid plaques. The human microglial response also involves a pro-inflammatory cytokine/chemokine CRM response to oligomeric Aβo. Genetic deletion of TREM2 or APOE, as well as APOE polymorphisms and TREM2R47H expression in the transplanted microglia modulate these responses differentially. The expression of other AD risk genes is differentially regulated across the distinct cell states elicited in response to amyloid pathology. Thus, we have identified multiple transcriptomic cell states adopted by human microglia in response to AD-related pathology, which should be taken into account in translational studies.

2024-02-29 | GSE216999 | GEO

Novel Alzheimer risk genes determine the microglia response to amyloid-β but not to TAU pathology

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

Novel Alzheimer risk genes determine the microglia response to amyloid-β but not to TAU pathology

2020-01-14 | GSE110741 | GEO

Transcriptomic and functional deficits in human TREM2-/- microglia impair response to Alzheimer's pathology in vivo [scRNA-seq]

Project description:scRNA-sequencing of human xenotransplanted microglia isogenic for TREM2 after exposure to amyloid pathology

2020-09-19 | GSE158234 | GEO

APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia

Project description:The major genetic risk factor for Alzheimer’s disease (AD), APOE4, accelerates beta-amyloid (Aβ) plaque formation, but whether this is caused by APOE expressed in microglia or astrocytes is debated. We express here the human APOE isoforms in astrocytes in an Apoe-deficient AD mouse model. This is not only sufficient to restore the amyloid plaque pathology but also induces the characteristic transcriptional pathological responses in Apoe-deficient microglia surrounding the plaques. We find that both APOE4 and the protective APOE2 from astrocytes increase fibrillar plaque deposition, but differentially affect soluble Aβ aggregates. Microglia and astrocytes show specific alterations in function of APOE genotype expressed in astrocytes. Our experiments indicate a central role of the astrocytes in APOE mediated amyloid plaque pathology and in the induction of associated microglia responses.

2024-10-04 | GSE252454 | GEO

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