Project description:Microglia, the brain’s primary resident immune cells, can assume various phenotypes with diverse functional outcomes on brain homeostasis. In Alzheimer’s disease (AD), where microglia are a leading causal cell type, the identity of microglia subsets that drive neurodegeneration remains unresolved. Here, we identify a microglia phenotype characterized by a conserved stress signaling pathway, the integrated stress response (ISR). Using mouse models to activate or inhibit ISR in microglia, we show that ISR underlies the ultrastructurally distinct “dark” microglia subset linked to pathological synapse loss. Inducing microglial ISR in murine AD models exacerbates neurodegenerative pathologies, such as Tau pathology and synaptic terminal loss. Conversely, inhibiting microglial ISR in AD models ameliorates these pathologies. Mechanistically, we present evidence that ISR promotes the secretion of toxic long- chain lipids that impair neuron and oligodendrocyte homeostasis in vitro. Accordingly, inhibition of lipid synthesis in AD models ameliorates synaptic terminal loss. Our results demonstrate that activation of ISR within microglia represents a pathway contributing to neurodegeneration and suggest that this may be sustained, at least in part, by the secretion of long-chain lipids from ISR-activated microglia.
Project description:Microglia, the brain’s primary resident immune cells, can assume various phenotypes with diverse functional outcomes on brain homeostasis. In Alzheimer’s disease (AD), where microglia are a leading causal cell type, the identity of microglia subsets that drive neurodegeneration remains unresolved. Here, we identify a microglia phenotype characterized by a conserved stress signaling pathway, the integrated stress response (ISR). Using mouse models to activate or inhibit ISR in microglia, we show that ISR underlies the ultrastructurally distinct “dark” microglia subset linked to pathological synapse loss. Inducing microglial ISR in murine AD models exacerbates neurodegenerative pathologies, such as Tau pathology and synaptic terminal loss. Conversely, inhibiting microglial ISR in AD models ameliorates these pathologies. Mechanistically, we present evidence that ISR promotes the secretion of toxic long- chain lipids that impair neuron and oligodendrocyte homeostasis in vitro. Accordingly, inhibition of lipid synthesis in AD models ameliorates synaptic terminal loss. Our results demonstrate that activation of ISR within microglia represents a pathway contributing to neurodegeneration and suggest that this may be sustained, at least in part, by the secretion of long-chain lipids from ISR-activated microglia.
Project description:Aging is the predominant risk factor for neurodegenerative diseases. One key phenotype as brain ages is the aberrant innate immune response characterized by proinflammation. However, the molecular mechanisms underlying aging-associated proinflammation are poorly defined. Whether chronic inflammation plays a causal role in cognitive decline in aging and neurodegeneration has not been established. Here we established a mechanistic link between chronic inflammation and aging microglia, and demonstrated a causal role of aging microglia in neurodegenerative cognitive deficits. Expression of microglial SIRT1 reduces with the aging of microglia. Genetic reduction of microglial SIRT1 elevates IL-1β selectively, and exacerbates cognitive deficits in aging and in transgenic mouse models of frontotemporal dementia (FTD). Interestingly, the selective activation of IL-1β transcription by SIRT1 deficiency is likely mediated through hypomethylating the proximal promoter of IL-1β. Consistent with our findings in mice, selective hypomethylation of IL-1β at two CpG sites are found in normal aging humans and demented patients with tauopathy. Our findings reveal a novel epigenetic mechanism in aging microglia that contributes to cognitive deficits in neurodegenerative diseases. Study of changes related to alterations of SIRT1 levels in microglia of young and aged animals and in models of neurodegenerative dementia
Project description:Traumatic Brain injury-induced disturbances in mitochondrial fission-and-fusion dynamics have been linked to the onset and propagation of neuroinflammation and neurodegeneration. However, cell-type-specific contributions and crosstalk between neurons, microglia, and astrocytes in mitochondria-driven neurodegeneration after brain injury remain undefined. We developed a human three-dimensional in vitro triculture tissue model of a contusion injury composed of neurons, microglia, and astrocytes and examined the contributions of mitochondrial dysregulation to neuroinflammation and progression of injury-induced neurodegeneration. Pharmacological studies presented here suggest that fragmented mitochondria released by microglia are a key contributor to secondary neuronal damage progression after contusion injury, a pathway that requires astrocyte-microglia crosstalk. Controlling mitochondrial dysfunction thus offers an exciting option for developing therapies for TBI patients.
Project description:Aging is the predominant risk factor for neurodegenerative diseases. One key phenotype as brain ages is the aberrant innate immune response characterized by proinflammation. However, the molecular mechanisms underlying aging-associated proinflammation are poorly defined. Whether chronic inflammation plays a causal role in cognitive decline in aging and neurodegeneration has not been established. Here we established a mechanistic link between chronic inflammation and aging microglia, and demonstrated a causal role of aging microglia in neurodegenerative cognitive deficits. Expression of microglial SIRT1 reduces with the aging of microglia. Genetic reduction of microglial SIRT1 elevates IL-1β selectively, and exacerbates cognitive deficits in aging and in transgenic mouse models of frontotemporal dementia (FTD). Interestingly, the selective activation of IL-1β transcription by SIRT1 deficiency is likely mediated through hypomethylating the proximal promoter of IL-1β. Consistent with our findings in mice, selective hypomethylation of IL-1β at two CpG sites are found in normal aging humans and demented patients with tauopathy. Our findings reveal a novel epigenetic mechanism in aging microglia that contributes to cognitive deficits in neurodegenerative diseases.
Project description:In this study, we used single-cell RNA-sequencing to gain unprecedented insight into the phenotypic heterogeneity and the transcriptional dynamics of microglia cells during the progression of neurodegeneration. Briefly, by using a severe neurodegeneration mouse model with Alzheimer’s-like pathology and phenotypes (CK-p25 model), we surveyed microglia activation by RNA sequencing longitudinally at fine temporal- and single-cell resolution. In summary, our work identified previously unobserved heterogeneity in the response of microglia to neurodegeneration, discovered novel microglia cell states, revealed the trajectory of cellular reprogramming of microglia in response to neurodegeneration, and uncovered the underlying transcriptional programs. These insights into the molecular programs underlying microglia activation provided by our study may pave the way for designing new rational and efficient strategies to treat Alzheimer’s and other neurodegenerative diseases.
Project description:L-Histiocytosis is a clonal myeloid disease characterized by BRAFV600E somatic mutations and increased risk of neurodegeneration, the mechanism of which is poorly understood. We report that microglia from histiocytosis patients is characterized by a high mutational load, dominated by the BRAFV600E variant. Genetic bar-coding analysis of the patients’ microglia, blood and/or bone marrow suggest that most microglia clones are generated or expanded locally. A diagnosis of neurodegeneration was linked to larger and more widespread clusters of mutant microglia. Microglial clones preferentially accumulate in the patients’ hippocampus and brainstem, attributable in part to a local proliferative advantage over time in mouse models. snRNAseq showed that BRAFV600E microglia cause neuro-inflammation, a neurotoxic astrocyte response, and preferential loss of pons glutamatergic and GABAergic neurons. Early treatment with CSF1R-inhibitor depleted mutant microglia, limited neuronal loss, improved symptoms, and prolonged survival in mice, suggesting that preventive treatment may alleviate neurodegeneration in Histiocytosis.