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A neurotoxic cellular stress response linked to dark microglia and toxic lipid secretion

ABSTRACT:

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 discover that a conserved stress signaling pathway, the integrated stress response (ISR), characterizes a subset of microglia with neurodegenerative outcomes. ISR is activated in AD-associated microglia subsets, including the ultrastructurally distinct “dark” microglia linked to pathological synapse loss. Activation of ISR in microglia is sufficient to induce early features of dark microglia. In AD models, microglial ISR exacerbates neurodegenerative pathologies, such as Tau and synapse loss, while inhibiting microglial ISR ameliorates them. Mechanistically, we present evidence that ISR in microglia promotes the secretion of toxic long-chain lipids that impair neuron homeostasis and survival in vitro. Accordingly, pharmacological inhibition of ISR and lipid synthesis ameliorates synapse loss in AD models. 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 toxic long-chain lipids from ISR-activated microglia.

INSTRUMENT(S): Direct infusion MS - positive

PROVIDER: MTBLS11942 | MetaboLights | 2024-12-20

REPOSITORIES: MetaboLights

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Project description:Microglia are innate immune cells of the brain that perform phagocytic and inflammatory functions in disease conditions. Transcriptomic studies of acutely-isolated microglia have provided novel insights into their molecular and functional diversity in homeostatic and neurodegenerative disease states. State-of-the-art mass spectrometric methods can comprehensively characterize proteomic alterations in microglia in neurodegenerative disorders, potentially providing novel functionally-relevant molecular insights that are not provided by transcriptomics. However, proteomic profiling of adult primary microglia in neurodegenerative disease conditions has not been performed. We performed quantitative proteomic analyses of purified CD11b+ acutely-isolated microglia adult mice in normal, acute neuroinflammatory (LPS-treatment) and chronic neurodegenerative states (5xFAD model of Alzheimer’s disease [AD]) using tandem mass tag mass spectrometry. Differential expression analyses were performed to characterize specific microglial proteomic changes in 5xFAD mice and identify overlap with LPS-induced pro-inflammatory changes. Our results were also contrasted with existing proteomic data from wild-type mouse microglia and from existing microglial transcriptomic data from wild-type and 5xFAD mice. Neuropathological validation studies of select proteins were performed in human AD and 5xFAD brains. Of 4,133 proteins identified, 187 microglial proteins were differentially expressed in the 5xFAD mouse model of AD pathology, including proteins with previously known (Apoe, Clu and Htra1) as well as previously unreported relevance to AD biology (Cotl1 and Hexb). Proteins upregulated in 5xFAD microglia shared significant overlap with pro-inflammatory changes observed in LPS-treated mice. Several proteins increased in human AD brain were also upregulated by 5xFAD microglia (Aβ peptide, Apoe, Htra1, Cotl1 and Clu). Cotl1 was identified as a novel microglia-specific marker with increased expression and strong association with AD neuropathology. Apoe protein was also detected within plaque-associated microglia in which Apoe and Aβ were highly co-localized suggesting a role for Apoe in phagocytic clearance of Aβ. We report the first comprehensive comparative proteomic study of adult mouse microglia derived from acute neuroinflammatory and AD models, representing a valuable resource to the neuroscience research community. We highlight shared and unique microglial proteomic changes in acute neuroinflammatory, aging and AD mouse models in addition to identifying novel roles for microglial proteins in human neurodegeneration.

			Action	DRS
	DMSO_1.mzML	Mzml
	DMSO_2.mzML	Mzml
	DMSO_3.mzML	Mzml
	DMSO_4.mzML	Mzml
	DMSO_5.mzML	Mzml

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A neurotoxic cellular stress response linked to dark microglia and toxic lipid secretion

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