Plaque-induced transcriptional reprogramming of microglia towards lymphoid receptor expression protects against Alzheimer's disease
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE296523 | GEO | 2025/08/07
REPOSITORIES: GEO
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Project description:Microglia, the innate immune cells of the brain, play a defining role in the progression of Alzheimer’s disease (AD). The microglial response to amyloid plaques can be either neuroprotective or neurotoxic. Here we show that the protective function of microglia is associated with and functionally linked to a transcriptional shift toward lymphoid gene expression. Microglial contact with the plaques induces downregulation of PU.1, a lineage-specifying transcription factor. PU.1 downregulation plays a key role in mitigating the severity of AD, as evidenced by a reduction in neurotoxic microglia activation, preservation of neuronal connections, maintenance of cognitive function, and increased survival in mice with genetically reduced PU.1 expression in microglia. The neuroprotective effect of PU.1 downregulation is linked to the de-repression of lymphoid-specific proteins, particularly CD28—a surface protein critical for T cell activation. Microglia-specific deficiency in CD28, which is expressed exclusively in a small subset of plaque-associated PU.1low microglia, promotes an inflammatory microglial state and associated increase in amyloid plaque load. Our findings suggest that PU.1low lymphoid/CD28-expressing microglia that emerge in response to AD pathology exert a suppressive, anti-inflammatory effect during AD. This novel role of CD28 -and potentially other lymphoid co-stimulatory or co-inhibitory receptor proteins- in governing microglia responses in AD points to possible new immunotherapy approaches for AD treatment.
2025-08-07 | GSE296641 | GEO
Project description:Microglia, the innate immune cells of the brain, play a defining role in the progression of Alzheimer’s disease (AD). The microglial response to amyloid plaques can be either neuroprotective or neurotoxic. Here we show that the protective function of microglia is associated with and functionally linked to a transcriptional shift toward lymphoid gene expression. Microglial contact with the plaques induces downregulation of PU.1, a lineage-specifying transcription factor. PU.1 downregulation plays a key role in mitigating the severity of AD, as evidenced by a reduction in neurotoxic microglia activation, preservation of neuronal connections, maintenance of cognitive function, and increased survival in mice with genetically reduced PU.1 expression in microglia. The neuroprotective effect of PU.1 downregulation is linked to the de-repression of lymphoid-specific proteins, particularly CD28—a surface protein critical for T cell activation. Microglia-specific deficiency in CD28, which is expressed exclusively in a small subset of plaque-associated PU.1low microglia, promotes an inflammatory microglial state and associated increase in amyloid plaque load. Our findings suggest that PU.1low lymphoid/CD28-expressing microglia that emerge in response to AD pathology exert a suppressive, anti-inflammatory effect during AD. This novel role of CD28 -and potentially other lymphoid co-stimulatory or co-inhibitory receptor proteins- in governing microglia responses in AD points to possible new immunotherapy approaches for AD treatment.
2025-08-07 | GSE275026 | GEO
Project description:Microglia, the innate immune cells of the brain, play a defining role in the progression of Alzheimer’s disease (AD). The microglial response to amyloid plaques can be either neuroprotective or neurotoxic. Here we show that the protective function of microglia is associated with and functionally linked to a transcriptional shift toward lymphoid gene expression. Microglial contact with the plaques induces downregulation of PU.1, a lineage-specifying transcription factor. PU.1 downregulation plays a key role in mitigating the severity of AD, as evidenced by a reduction in neurotoxic microglia activation, preservation of neuronal connections, maintenance of cognitive function, and increased survival in mice with genetically reduced PU.1 expression in microglia. The neuroprotective effect of PU.1 downregulation is linked to the de-repression of lymphoid-specific proteins, particularly CD28—a surface protein critical for T cell activation. Microglia-specific deficiency in CD28, which is expressed exclusively in a small subset of plaque-associated PU.1low microglia, promotes an inflammatory microglial state and associated increase in amyloid plaque load. Our findings suggest that PU.1low lymphoid/CD28-expressing microglia that emerge in response to AD pathology exert a suppressive, anti-inflammatory effect during AD. This novel role of CD28 -and potentially other lymphoid co-stimulatory or co-inhibitory receptor proteins- in governing microglia responses in AD points to possible new immunotherapy approaches for AD treatment.
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Project description:Amyloid plaques, a hallmark of Alzheimer's disease (AD), combine chemical and physical properties foreign to normal brain tissue. These "non-self" plaque patterns trigger local tissue responses in the brain, including microglia activation. Microglial response to the plaques can be both protective, aiming at amyloid clearance and neuroprotection, and harmful, associated with microglia-driven inflammation and neurotoxicity. Here, we provide evidence that the microglial neuroprotective response to amyloid plaques involves a relaxation of the microglia lineage specification toward a lymphoid-like state. We found that a subpopulation of plaque-associated microglia downregulates the microglia lineage-specifying transcription factor PU.1 and de-represses several lymphoid-expressed genes, including those that play a key role in receptor-mediated signaling in B and T lymphocytes. The shift toward the lymphoid lineage is associated with an increased signaling capacity of PU.1low microglia that supports microglia maintenance at the plaque. Functionally, we show that PU.1low microglia protect neurons and reduce plaque-associated damage in a mouse model of amyloid deposition. Engineered genetic downregulation of PU.1 in microglia in the healthy brain emulates phenotypic features of plaque-associated microglia, promotes microglia-plaque association in disease, and protects against the loss of functional neuronal connections and associated behaviors, including cognition and memory in mice. We propose that the plaque-induced microglia lineage relaxation represents a novel mechanism of the microglial responses in the presence of AD pathology that is adaptive in nature and protective by function.
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Project description:Amyloid plaque associated microglia induce a transcriptional state characterized by downregulation of the transcription factor Spi1 and upregulation of a subset of canonically lymphoid-specific signaling genes. Knockout of one such gene, Cd28, in microglia exacerbates interferon-responses in response to amyloid pathology.
2025-08-07 | GSE296768 | GEO
Project description:Alzheimer's disease (AD) remainsis a prevalent major cause of senile dementia without effective therapeutic strategiesy. Although Recent studies highlight the critical role of microglia has been well accepted to play a critical role in AD pathology, particularly in the early stages, this study is the first breakthrough to show, suggesting that modulation of pathological microglial states represents a therapeutic opportunity. Here we provide evidence that microglial connexin 43 (Cx43) hemichannel is the main switch ofs regulate microglial reactivity in the context of AD, as well as a promising hence presenting a potential therapeutic target. We demonstrated a marked increase in Cx43 protein level in the periplaque microglia in the post-mortem tissue from AD patients. In APPswe/PS1dE9 mouse model, we discoveredfound that microglial Cx43 operates as a hemichannel to influence microglial function, which in turn affects in β-amyloid pathology. Ablation of microglial Cx43 hemichannels by genetic knockout screwed microglia to neuroprotective phenotype by promotinges the microglia-plaque interaction while suppressing the neurotoxic microglial signature, and thereby mitigating the progression of AD. Following this lead, wWe developed a novel formulation of small molecule peptide, treatment strategy employing lipid nanoparticle-delivered molecule TAT-Cx43266-283 (TAT-CX43@LNPs), which selectivespecifically targets blocks Cx43 hemichannels, and conducted a. Our preclinical trialstudy that demonstrated its efficacyeffectiveness in delaying and rescuing β-amyloid-related neuropathology and cognitive impairment in AD mice. This study provides strong evidence to progress our novel drug into clinical trials and translate it not only into a therapeutic agent during disease progression but also offer strong preventive benefits when administered early.
2025-05-22 | GSE272781 | GEO
Project description:Purpose: We purified spinal cord microglia utilizing percoll gradients and magnetic beads, followed by transcriptome profiling (RNA-seq) to define microglia expression profiles against other neural, immune cell-types. We next observed how the microglial transcriptomes change during activation in the SOD1-G93A mouse model of motor neuron degeneration at 3 time points. We also compared these profiles with that induced by LPS injection. Results and conclusions: ALS microglia were found to differ substantially from those activated by LPS and from M1/M2 macrophages by comparison with published datasets. These ALS microglia showing substantial induction of a neurodegeneration-tailored phenotype, with induction of lysosomal, RNA splicing, and Alzheimer's disease pathway genes. Overall they express a mixture of neuroprotective and neurotoxic factors during activation in ALS mice, showing that neuro-immune activation in the spinal cord is a double-edged sword. We also detected the transcriptional nature of surface marker expression in microglia (CD11b, CD86, CD11c), and substantial T-cell microglia cross-talk using correlative microglia transcriptome/FACS analysis. 42 total RNA samples from purified spinal cord microglia were subjected to paired-end RNA-sequencing. Parallel flow cytometry data was collected from the same spinal cords.
2013-07-15 | E-GEOD-43366 | 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: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
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