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PILRA regulates microglial neuroinflammation and lipid metabolism as a candidate therapeutic target for Alzheimer’s disease

ABSTRACT: PILRA regulates microglial neuroinflammation and lipid metabolism as a candidate therapeutic target for Alzheimer’s disease

PROVIDER: PRJNA1075317 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27937400.fastq.gz	Fastqsanger.gz
	SRR27937401.fastq.gz	Fastqsanger.gz
	SRR27937402.fastq.gz	Fastqsanger.gz
	SRR27937403.fastq.gz	Fastqsanger.gz
	SRR27937404.fastq.gz	Fastqsanger.gz

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Project description:Alzheimer’s disease is associated with disrupted circadian rhythms and clock gene expression. REV-ERBα (Nr1d1) is a circadian transcriptional repressor involved in the regulation of lipid metabolism and macrophage function. While global REV-ERBα deletion increases microglial activation and mitigates amyloid plaque formation, the cell-autonomous effects of microglial REV-ERBα deletion in healthy brain and in tauopathy are unexplored. Here, we show that microglial REV-ERBα deficient enhances inflammatory signaling, disrupts lipid metabolism, and causes lipid droplet (LD) accumulation specifically in male microglia. Inflammation and LD accumulation combine to inhibit microglial tau phagocytosis, which can be partially rescued by blockage of lipid droplet formation. Microglial REV-ERBα deletion exacerbates tau aggregation and neuroinflammation in P301S and AAV-P301L tauopathy models in male, but not female mice. These data demonstrate the importance of microglial lipid droplets in tau accumulation and reveal REV-ERBα as a therapeutically accessible, sex-dependent regulator of microglial inflammatory signaling, lipid metabolism, and tauopathy.

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Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy

Project description:Alzheimer’s disease is associated with disrupted circadian rhythms and clock gene expression. REV-ERBα (Nr1d1) is a circadian transcriptional repressor involved in the regulation of lipid metabolism and macrophage function. While global REV-ERBα deletion increases microglial activation and mitigates amyloid plaque formation, the cell-autonomous effects of microglial REV-ERBα on tau pathology are unexplored. Here, we show that microglial REV-ERBα deletion enhances inflammatory signaling, disrupts lipid metabolic processes, and causes lipid droplet (LD) accumulation specifically in male microglia. Inflammation and LD accumulation combine to inhibit microglial tau phagocytosis, which can be partially rescued by blockage of lipid droplet formation. Microglial REV-ERBα deletion exacerbates tau aggregation and neuroinflammation in P301S and AAV-P301L tauopathy models in male, but not female mice. These data demonstrate the importance of microglial lipid droplets in tau accumulation and reveal REV-ERBα as a therapeutically accessible, sex-dependent regulator of microglial inflammatory signaling, lipid metabolism, and tauopathy.

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PILRA regulates microglial neuroinflammation and lipid metabolism as a candidate therapeutic target for Alzheimer’s disease

Project description:This study seeks to test how PILRA KO affects human microglial response to AD pathology in vivo using a xenotransplant mouse model of AD and single-cell RNA-sequencing.

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Project description:Alzheimer’s disease (AD) is characterized by amyloid plaques and neurofibrillary tangles in addition to neuroinflammation and changes in brain lipid metabolism. Recent findings have demonstrated that microglia are key drivers of neurodegeneration in tauopathy mouse models. A subset of microglia referred to as disease-associated microglia (DAM) display gene signatures signifying changes in proinflammatory signaling and lipid metabolism in mouse models of amyloid and tau pathology. Ch25h is a DAM gene encoding cholesterol 25-hydroxylase that produces 25-hydroxycholesterol (25HC), a known modulator of inflammation as well as lipid metabolism. However, whether Ch25h influences tau-mediated neuroinflammation and neurodegeneration is unknown. Here, we show that in the absence of Ch25h and 25HC there is strikingly reduced age-dependent neurodegeneration and neuroinflammation in the hippocampus and entorhinal/piriform cortex of PS19 mice which express the P301S mutant human tau transgene. Transcriptomic analyses of bulk hippocampal tissue and single nuclei revealed that Ch25h deficiency in PS19 mice strongly suppressed proinflammatory cytokine and chemokine signaling in microglia and restored sterol synthesis. Our results suggest a key role for Ch25h/25HC in potentiating proinflammatory signaling to promote tau-mediated neurodegeneration. Ch25h may represent a novel therapeutic target for primary tauopathies, AD, and other neuroinflammatory diseases.

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Project description:Metabolic reprogramming is often observed in sepsis-associated encephalopathy (SAE). However, little is known about the aberrant metabolic genes involved in mitochondrial damage, neuroinflammation, and lipid accumulation in microglial cells. Here, we show that hexokinase 2 (HK2) is upregulated and is strongly associated with the inflammatory response and lipid metabolism in lipopolysaccharide-induced BV2 cells. Genetic silencing or pharmacological inhibition of HK2 attenuates mitochondrial damage in vitro. Downregulation of HK2 lowered the NOD-like receptor signaling family pyrin domain containing three activations, both in BV2 cells and in the hippocampus of cecal ligation and puncture-induced male septic mice. Moreover, the inhibition of HK2 promoted lipid droplet reduction and activated mammalian target of rapamycin-mediated autophagy. Mechanistically, HK2 knockdown in microglial cells reduced the ISGylation of Acyl-CoA Synthetase Long-chain Family Member 4 (ACSL4) during lipid metabolism by interferon-stimulated gene 15 (ISG15). Notably, ISG15 eﬀectively down-regulated the expression of ACSL4 in vitro. Our findings provide new mechanistic insights of HK2 in microglial cells through regulation of ACSL4 ISGylation, suggesting a promising therapeutic strategy for treating SAE by targeting HK2.

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