Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA682202 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13186687.fastq.gz | Fastqsanger.gz | |||
| SRR13186688.fastq.gz | Fastqsanger.gz | |||
| SRR13186689.fastq.gz | Fastqsanger.gz | |||
| SRR13186690.fastq.gz | Fastqsanger.gz | |||
| SRR13186691.fastq.gz | Fastqsanger.gz |
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Project description:More than forty loci contribute to genetic risk for Alzheimer’s disease (AD). These risk alleles are enriched in myeloid cell enhancers suggesting that microglia, the brain-resident macrophages, contribute to AD risk. We have previously identified SPI1/PU.1, a master regulator of myeloid cell development in the brain and periphery, as a genetic risk factor for AD. Higher expression of SPI1 is associated with increased risk for AD, while lower expression is protective. To investigate the molecular and cellular phenotypes associated with higher and lower expression of PU.1 in microglia, we used stable overexpression and knock-down of PU.1 in BV2, an immortalized mouse microglial cell line. Transcriptome analysis suggests that reduced PU.1 expression suppresses expression of homeostatic genes similar to the disease-associated microglia response to amyloid plaques in mouse models of AD. Moreover, PU.1 knock-down resulted in activation of protein translation, antioxidant action and cholesterol/lipid metabolism pathways with a concomitant decrease of pro-inflammatory gene expression. PU.1 overexpression upregulated and knock-down downregulated phagocytic uptake in BV2 cells independent of the nature of the engulfed material. However, cells with reduced PU.1 expression retained their ability to internalize myelin similar to control albeit with a delay, which aligns with their anti-inflammatory profile. Here we identified several microglial responses that are modulated by PU.1 expression levels and propose that risk association of PU.1 to AD is driven by increased pro-inflammatory response due to increased viability of cells under cytotoxic conditions. In contrast, low expression of PU.1 leads to increased cell death under cytotoxic conditions accompanied by reduced pro-inflammatory signaling that decreased A1 reactive astrocytes signature supporting the protective effect of SPI1 genotype in AD. These findings inform future in vivo validation studies and design of small molecule screens for therapeutic discovery in AD.
2020-12-07 | GSE162526 | GEO
Project description:More than forty loci contribute to genetic risk for Alzheimer's disease (AD). These risk alleles are enriched in myeloid cell enhancers suggesting that microglia, the brain-resident macrophages, contribute to AD risk. We have previously identified SPI1/PU.1, a master regulator of myeloid cell development in the brain and periphery, as a genetic risk factor for AD. Higher expression of SPI1 is associated with increased risk for AD, while lower expression is protective. To investigate the molecular and cellular phenotypes associated with higher and lower expression of PU.1 in microglia, we used stable overexpression and knock-down of PU.1 in BV2, an immortalized mouse microglial cell line. Transcriptome analysis suggests that reduced PU.1 expression suppresses expression of homeostatic genes similar to the disease-associated microglia response to amyloid plaques in mouse models of AD. Moreover, PU.1 knock-down resulted in activation of protein translation, antioxidant action and cholesterol/lipid metabolism pathways with a concomitant decrease of pro-inflammatory gene expression. PU.1 overexpression upregulated and knock-down downregulated phagocytic uptake in BV2 cells independent of the nature of the engulfed material. However, cells with reduced PU.1 expression retained their ability to internalize myelin similar to control albeit with a delay, which aligns with their anti-inflammatory profile. Here we identified several microglial responses that are modulated by PU.1 expression levels and propose that risk association of PU.1 to AD is driven by increased pro-inflammatory response due to increased viability of cells under cytotoxic conditions. In contrast, low expression of PU.1 leads to increased cell death under cytotoxic conditions accompanied by reduced pro-inflammatory signaling that decreased A1 reactive astrocytes signature supporting the protective effect of SPI1 genotype in AD. These findings inform future in vivo validation studies and design of small molecule screens for therapeutic discovery in AD.
| S-EPMC7808757 | biostudies-literature
Project description:SPI1 (PU.1) was recently reported as a genetic risk factor of Alzheimer’s disease (AD) in large-scale genome-wide association studies (GWAS). However, it is unknown whether PU.1 should be downregulated or increased to have therapeutic benefits. This is a critical question that must be answered before initiating any drug discovery project. To investigate the effect of modulating PU.1 level on AD pathology, we performed biochemical, histological, transcriptomic, and proteomic analyses using PU.1-knockdown and overexpression mouse models. PU.1-knockdown markedly increased amyloid-b (Ab) levels, amyloid plaque deposition, and gliosis. Conversely, PU.1-overexpression significantly decreased Ab levels, amyloid plaque deposition, gliosis, and dystrophic neurites. Furthermore, we identified several biological pathways, such as immune response pathways and complement system, regulated by the altered PU.1 expression through the analyses of proteomics as well as bulk and single-cell transcriptomics data. Our data provide crucial in vivo data to guide future therapeutic strategies for AD.
2024-03-18 | GSE222624 | GEO
Project description:SPI1 (PU.1) was recently reported as a genetic risk factor of Alzheimer’s disease (AD) in large-scale genome-wide association studies (GWAS). However, it is unknown whether PU.1 should be downregulated or increased to have therapeutic benefits. This is a critical question that must be answered before initiating any drug discovery project. To investigate the effect of modulating PU.1 level on AD pathology, we performed biochemical, histological, transcriptomic, and proteomic analyses using PU.1-knockdown and overexpression mouse models. PU.1-knockdown markedly increased amyloid-b (Ab) levels, amyloid plaque deposition, and gliosis. Conversely, PU.1-overexpression significantly decreased Ab levels, amyloid plaque deposition, gliosis, and dystrophic neurites. Furthermore, we identified several biological pathways, such as immune response pathways and complement system, regulated by the altered PU.1 expression through the analyses of proteomics as well as bulk and single-cell transcriptomics data. Our data provide crucial in vivo data to guide future therapeutic strategies for AD.
2024-03-18 | GSE225669 | GEO
Project description:Microglia are versatile regulators in brain development and disorders. Emerging evidence links miRNA-mediated regulation to microglial function; however, the exact underlying mechanism remains largely unknown. Here, we discover that miR-137, a neuropsychiatric disorders-associated miRNA, is abundant in the microglial nucleus and exhibits unexpected epigenetic functions in maintaining the global transcriptomic state, core properties, and functions of microglia. Mechanistically, microglial Mir137 deletion increases the accessibility of chromatin, which harbors binding motifs of microglial master transcription factor Pu.1. Our biochemical and bioinformatics analyses suggest that miR-137 can interact with Pu.1, thus influencing Pu.1-mediated gene expression. Importantly, we find that increased Pu.1 binding upregulates the target gene Jdp2, and Jdp2 knockdown markedly suppresses the impaired cellular phenotypes in Mir137 knockout microglia. Collectively, our study provides evidence supporting a notion that miR-137 acts as an epigenetic regulator, and this microglia-specific function is essential to maintain normal adult brain function.
2024-02-22 | GSE254802 | GEO
Project description:In Alzheimer’s disease (AD), sensome receptor dysfunction impairs microglial danger-associated molecular pattern (DAMP) clearance and exacerbates disease pathology. While extrinsic signals including interleukin-33 (IL-33) can restore microglial DAMP clearance, it remains largely unclear how the sensome receptor(s) is regulated and interacts with DAMP during phagocytic clearance. Here, we show that IL-33 induces VCAM1 in microglia, which promotes microglial chemotaxis toward amyloid-beta (Aβ) plaque-associated ApoE, and leads to Aβ clearance. We show that IL-33 stimulates a chemotactic state in microglia, characterized by Aβ-directed migration. Functional screening identified that VCAM1 directs microglial Aβ chemotaxis by sensing Aβ plaque-associated ApoE. Moreover, we found that disrupting VCAM1–ApoE interaction abolishes microglial Aβ chemotaxis, resulting in decreased microglial clearance of Aβ. In patients with AD, higher cerebrospinal fluid levels of soluble VCAM1 were correlated with impaired microglial Aβ chemotaxis. Together, our findings demonstrate that promoting VCAM1–ApoE-dependent microglial functions ameliorates AD pathology.
2023-07-18 | GSE208006 | GEO
Project description:Impairment of microglial clearance activity contributes to beta-amyloid (Aβ) pathology in Alzheimer disease (AD). While the transcriptome profile of microglia directs microglial functions, how the microglial transcriptome can be regulated to alleviate AD pathology is largely unknown. Here, we show that injection of interleukin (IL)-33 in an AD transgenic mouse model ameliorates Aβ pathology by reprogramming microglial epigenetic and transcriptomic profiles to induce a microglial subpopulation with enhanced phagocytic activity. These IL-33–responsive microglia (IL-33RM) express distinct transcriptome signature, highlighted by major histocompatibility complex class II genes, and restored homeostatic signature genes. IL-33–induced remodeling of chromatin accessibility and PU.1 transcription factor binding at the signature genes of IL-33RM control their transcriptome reprogramming. Specifically, disrupting PU.1–DNA interaction abolishes the microglial state transition and Aβ clearance induced by IL-33. Thus, we define a PU.1-dependent transcriptional pathway that drives the IL-33–induced functional state transition of microglia, resulting in enhanced Aβ clearance.
2020-05-01 | GSE147495 | GEO
Project description:Despite the discovery of PMX205 more than 20 years ago and its reported beneficial effects in Alzheimer’s disease, the specific mechanism that might be driving the improvement in cognition are still not know. Here, we used the Tg2576 mouse model of Alzheimer’s disease and treated them with PMX205 at the onset of the amyloid pathology to further determine the effects of this C5aR1 antagonist on microglial cells. The results presented in this study demonstrated a neuroprotective effect of PMX205, which rescues the excessive synaptic pruning and synapse loss associated with Alzheimer’s disease. This finding seems to be linked to the reduction of a unique microglial subpopulation associated to synaptic pruning in the PMX205 treated mice. Interestingly, we also show here that blocking C5a-C5aR1 signaling in the Tg2576 mouse model of AD results in the increase of the DAM2 microglial subpopulation, suggesting that PMX205 might be inducing a disease mitigating phenotype on microglial cells. Our data further supports the use of C5aR1 antagonists as potential therapeutic targets to treat or slow the progression of Alzheimer’s disease.
2022-05-02 | GSE200942 | GEO
Project description:Lipopolysaccharide-dependent transcriptional regulation of PU.1 in microglial cells
| PRJNA556190 | ENA
Project description:Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by progressive decline of cognitive ability. An important component of AD, and other chronic neurodegenerative diseases, is generation of an innate inflammatory response within the CNS, characterized by activation of microglia, the resident immune cells of the brain. Transcription factor PU.1 has been known to play an important role in myeloid and lymphoid cell development, however its function in microglia and how it contributes to disease pathology is not well understood. Using transcriptional and chromatin state profiles during AD-like pathology in the CK-p25 mouse model of neurodegeneration, we showed that PU.1 specifically targets noncoding regions which regulate expression changes of immune response genes during AD, suggesting it may act as master regulator of microglia activation. Here, we examine the role of PU.1 in neurodegeneration by using a conditional knockout (cKO) cassette (Cx3cr1CreER+/-) to inducibly deplete PU.1 from microglia in the CK-p25 mouse model of neurodegeneration. We found that knocking out PU.1 rescues multiple neurodegenerative phenotypes. Specifically, PU.1 inhibition reduces neurodegeneration-specific increase in microglia cell number, improves neuronal survival and reverses functional synaptic plasticity deficits in the hippocampus of the CK-p25 mouse.
2021-01-01 | GSE117868 | GEO