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Plaque-induced transcriptional reprogramming of microglia towards lymphoid receptor expression protects against Alzheimer's disease

ABSTRACT: Plaque-induced transcriptional reprogramming of microglia towards lymphoid receptor expression protects against Alzheimer's disease

PROVIDER: PRJNA1259806 | ENA |

REPOSITORIES: ENA

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Plaque-induced transcriptional reprogramming of microglia towards lymphoid receptor expression protects against Alzheimer's disease [scRNA-seq]

Project description:Plaque-induced transcriptional reprogramming of microglia towards lymphoid receptor expression protects against Alzheimer's disease [scRNA-seq]

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Plaque induced transcriptional reprogramming of microglia towards lymphoid receptor expression protects against Alzheimer's disease

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 | PXD063383 | Pride

Plaque-induced transcriptional reprogramming of microglia towards lymphoid receptor expression protects against Alzheimer's disease [scRNA-seq]

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

Plaque-induced transcriptional reprogramming of microglia towards lymphoid receptor expression protects against Alzheimer's disease

Project description:We have utilized a single nucleus sequencing approach using 10x Genomics snRNA-seq to understand the role of PU.1 expression level in the determination of microglia activation states relavent to Alzheimer's disease. Microglia have been shown to have both neuroprotective and neurotoxic functions during disease, however it remains to be understood how these states are regulated. This study provides new insights into the protective function of microglia mediated by a transcriptional shift toward lymphoid gene expression.

2025-08-07 | GSE296523 | GEO

Plaque-induced transcriptional reprogramming of microglia towards lymphoid receptor expression protects against Alzheimer’s disease.

Project description:Plaque-induced transcriptional reprogramming of microglia towards lymphoid receptor expression protects against Alzheimer’s disease.

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Plaque-induced transcriptional reprogramming of microglia towards lymphoid receptor expression protects against Alzheimer’s disease

Project description:Plaque-induced transcriptional reprogramming of microglia towards lymphoid receptor expression protects against Alzheimer’s disease

| PRJNA1260427 | ENA

Microglia lineage relaxation towards a lymphoid-like state protects against Alzheimer’s disease.

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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Plaque-induced transcriptional reprogramming of microglia towards lymphoid receptor expression protects against Alzheimer’s disease. [RNA-seq]

Project description:Plaque-induced transcriptional reprogramming of microglia towards lymphoid receptor expression protects against Alzheimer’s disease. [RNA-seq]

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Plaque-induced transcriptional reprogramming of microglia towards lymphoid receptor expression protects against Alzheimer’s disease

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