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Female-specific Cx3cr1-driven regulation of ALS and Alzheimer’s risk genes in tauopathy

ABSTRACT: By introducing haploinsufficiency of Cx3cr1 in the P301S (PS19) transgenic model of tau pathology, we report remarkable transcriptional changes, including crucial amyotrophic lateral sclerosis and Alzheimer’s disease risk genes, several of which showed co-expression, suggesting gene–gene interactions among these genetic risk factors.

ORGANISM(S): Mus musculus

PROVIDER: GSE305471 | GEO | 2026/03/09

REPOSITORIES: GEO

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Microglial 25-hydroxycholesterol mediates neuroinflammation and neurodegeneration in a tauopathy mouse model.

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.

2023-12-08 | GSE242896 | GEO

Cholesterol 25-hydroxylase mediates neuroinflammation and neurodegeneration in a mouse model of tauopathy

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 the resultant reduction in 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.

2024-02-23 | GSE250277 | GEO

Abundance of tRNA fragments in Tau-RNA complexes from Tau-mutant PS19 (human P301S Tau transgenic) mice hippocampus

Project description:We report the binding between tRNA fragments and Phosphorylated Tau pS396 from the hippocampus of WT controls and Tau-mutant PS19 (human P301S Tau transgenic) mice. We show tRNA fragments abundance in Tau-RNA complexes changes between the two groups. Specific tRNA fragment in the results of Real Time-qPCR were consistent with the small RNA microarray:5'tRF_GluCTC

2025-05-14 | GSE297027 | GEO

Longitudinal Proteomic Profiling Defines a Two-Stage Remodeling Trajectory of Tauopathy in PS19 Mice

Project description:Tauopathies, including Alzheimer’s disease (AD), are characterized by progressive synaptic dysfunction, neuroinflammation, and neuronal loss. Across neuropathological and in vivo imaging studies, tau pathology shows a consistently tight relationship with cognitive impairment and neurodegeneration, often exceeding correlations observed for amyloid plaque burden, highlighting tau as a central determinant of clinical decline[1]. However, the temporal molecular transitions that connect early synaptic vulnerability to later inflammatory amplification and neurodegeneration remain incompletely defined. Here, we performed a longitudinal, label-free data-independent acquisition (DIA) proteomic profiling of brain tissues from PS19 (P301S) tau transgenic mice at 5, 6, and 7 months of age, together with 5-month noncarrier littermate controls. Comparative analysis at 5 months confirmed early tau-associated alterations involving synaptic organization, cytoskeletal regulation, and stress-responsive signaling pathways, consistent with prior reports that synapse loss and microglial activation can precede mature tau tangles in P301S/PS19-related models[2-5]. Furthermore, longitudinal profiling identified 776 significantly altered proteins (FDR < 0.05) that segregated into four distinct temporal expression patterns. These trajectories delineate a two-stage disease course, with an initial adaptive phase (5–6 months) marked by synaptic down-tuning and metabolic stress responses, followed by a transition toward an inflammatory and degenerative state (6–7 months). Notably, 6 months emerged as a molecular transition point characterized by coordinated activation of stress-associated signaling pathways. This transition timing is consistent with PS19/P301S literature indicating prominent neurofibrillary tangles (NFT) pathology around ~6 months with subsequent neurodegenerative escalation[6].

2026-03-15 | PXD075656 |

Protein kinase CK2α’ as a Dual Modulator of Immune Signaling and Synaptic Dysfunction in Tauopathy

Project description:Protein kinase CK2α’ is upregulated in patients with tau-associated dementias and in the PS19 mouse model of tauopathy. CK2α’ haploinsufficiency in the PS19 mouse model improved tau pathology, synaptic density, synaptic function, cognitive behavior and disease-associated microglia phenotypes. We hypothesized CK2α’ haploinsufficiency would impact dysregulated gene expression in the PS19 model. We found that CK2α’ haploinsufficiency led to enhanced synaptic gene network expression and enhance immune gene network expression.

2026-02-06 | GSE298505 | GEO

Female-specific Cx3cr1-driven regulation of ALS and Alzheimer’s risk genes in tauopathy

Project description:Female-specific Cx3cr1-driven regulation of ALS and Alzheimer’s risk genes in tauopathy

| PRJNA1306045 | ENA

The inhibition of LSD1 via sequestration contributes to tau-mediated neurodegeneration

Project description:In this dataset, we evalute the effect of modulating the levels of LSD1 in the PS19 tauopathy mouse (mouse that expresses the P301S mutated form of the human tau transgene). First we reduced the levels of LSD1 by crossing PS19 Tau mice with mice heterozygous for Lsd1. This results in an exacerbation of the neurodegenerative phenotype as well as an increase in the transcripational changes observed in taupoathy mice. Secondy, we overexprssed LSD1 in neurons of the adult tauopathy mouse through viral injection direclty into the hippocampus. This resulted in a reduce of neuronal cell death as well as the associated transcriptional changes.

2020-10-27 | GSE160151 | GEO

LncRNA/mRNA sequencing analysis on cerebral cortex of P301S mutant Tau transgenic mice (PS19).

Project description:Aggregation of the microtubule-associated protein, tau, can lead to neurofibrillary tangle formation in neurons and glia, the hallmark of tauopathy. The cellular damages induced by the tau overexpression and aggregation may lead to multiple pathologic features of tauopathy. However, the effect of aging on tauopathy has not been elucidated yet. Here, we conducted lncRNA/mRNA sequencing analysis on P301S mutant Tau transgenic mouse model (PS19) with different ages to track the genetic changes occurred by the aging and progression of tau overexpression.

2019-06-23 | GSE118473 | GEO

Seed-competent tau monomer initiates pathology in PS19 tauopathy mice

Project description:Tau Monomer from age controlled healthy and Alzheimer's Disease LUM2_C10053 LUM2_C10054 LUM2_C10055 LUM2_C10056 LUM2_C10057 LUM2_C10058 Tau fibril from Alzheimer's Disease LUM2_630897 Tau monomer from brain of PS19 mouse at age week 1, 2, 3, 4, 5, 6 LUM1_C11496 to LUM1_C11501 Tau monomer from brain of PS19 mouse at age 1 year LUM1_705666

2022-01-06 | MSV000088651 | MassIVE

Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy [snRNA-Seq]

Project description:Activation of microglia is a prominent pathological feature in tauopathies, including Alzheimer’s disease. How microglia activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, activated by tau, drives microglial-mediated tau propagation and toxicity. Constitutive activation of microglial NF-κB exacerbated, while inactivation diminished, tau seeding and spreading in young PS19 mice. Inhibition of NF-B activation enhanced the retention while reduced the release of internalized pathogenic tau fibrils from primary microglia and rescued microglial autophagy deficits. Remarkably, inhibition of microglial NF-κB in aged PS19 mice rescued tau-mediated learning and memory deficits, restored overall transcriptomic changes while increasing neuronal tau inclusions. Single cell RNA-seq revealed that tau-associated disease states in microglia were diminished by NF-B inactivation and further transformed by constitutive NF-B activation. Our study establishes a central role for microglial NF-B signaling in mediating tau spreading and toxicity in tauopathy.

2022-03-10 | GSE198014 | GEO

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