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Multiomic single nuclei profiling of a mouse model of Alzheimer’s disease reveals that ACSS2 confers neuronal resilience to tauopathy

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE294332 | GEO | 2026/02/20

REPOSITORIES: GEO

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Multiomic single nuclei profiling of a mouse model of Alzheimer’s disease reveals that ACSS2 confers neuronal resilience to tauopathy [RNA-Seq]

Project description:Loss of cell identity and global epigenomic dysregulation are emerging as key contributors to Alzheimer’s disease (AD). The mechanisms by which protective or risk-conferring epigenetic marks are established and maintained are under intense investigation. ACSS2 (Acetyl-CoA Synthetase 2) is a key metabolic enzyme that is nuclear-localized in neurons. In healthy brains, ACSS2 fuels histone acetylation and drives expression of neuronal genes that regulate learning and memory. Here, we examine how loss of ACSS2 contributes to AD-associated cellular, genomic and behavioral outcomes, focusing on long-term steady state changes. Using a mouse model of human pathological AD-Tau injection, we show that loss of ACSS2 exacerbates Tau-related memory impairments, while dietary supplementation of acetate rescues learning in an ACSS2-dependent manner. Combining state-of-the-art proteomic and genomic approaches, we demonstrate that this effect is accompanied by ACSS2-dependent incorporation of acetate into hippocampal histone acetylation, which facilitates gene expression programs related to learning. We identify the most severely affected hippocampal neuronal populations, including pyramidal cells of the perforant pathway and Cajal-Retzius cells. Overall, these results reveal ACSS2 as a neuroprotective metabolic enzyme in key hippocampal neuronal populations, and dysregulation of which may play an important role in the etiology of AD. These findings may guide development of future therapies for AD, other tauopathies and related dementia.

2026-02-18 | GSE294261 | GEO

Multiomic single nuclei profiling of a mouse model of Alzheimer’s disease reveals that ACSS2 confers neuronal resilience to tauopathy [ChIP-seq]

2026-06-18 | GSE294751 | GEO

Multiomic single nuclei profiling of a mouse model of Alzheimer’s disease reveals that ACSS2 confers neuronal resilience to tauopathy [RNA-seq Acetate]

2026-06-18 | GSE294331 | GEO

Multiomic single nuclei profiling of a mouse model of Alzheimer’s disease reveals that ACSS2 confers neuronal resilience to tauopathy

Project description:Multiomic single nuclei profiling of a mouse model of Alzheimer’s disease reveals that ACSS2 confers neuronal resilience to tauopathy

| PRJNA1249036 | ENA

Multiomic single nuclei profiling of a mouse model of Alzheimer’s disease reveals that ACSS2 confers neuronal resilience to tauopathy [ChIP-seq]

Project description:Multiomic single nuclei profiling of a mouse model of Alzheimer’s disease reveals that ACSS2 confers neuronal resilience to tauopathy [ChIP-seq]

| PRJNA1251553 | ENA

Multiomic single nuclei profiling of a mouse model of Alzheimer’s disease reveals that ACSS2 confers neuronal resilience to tauopathy [RNA-Seq]

Project description:Multiomic single nuclei profiling of a mouse model of Alzheimer’s disease reveals that ACSS2 confers neuronal resilience to tauopathy [RNA-Seq]

| PRJNA1248894 | ENA

Multiomic single nuclei profiling of a mouse model of Alzheimer’s disease reveals that ACSS2 confers neuronal resilience to tauopathy [RNA-seq Acetate]

Project description:Multiomic single nuclei profiling of a mouse model of Alzheimer’s disease reveals that ACSS2 confers neuronal resilience to tauopathy [RNA-seq Acetate]

| PRJNA1249039 | ENA

Multiomic Evidence for a Unified Model of Alzheimer’s Disease Etiology Linking Microglial Flux Capacity and Astrocyte-Neuron Metabolic Breakdown

Project description: Not available

| S-EPMC12132299 | biostudies-literature

ZCCHC17 modulates neuronal RNA splicing and supports cognitive resilience in Alzheimer’s disease

Project description:ZCCHC17 is a zinc-finger protein previously identified as a regulator of synaptic gene expression which becomes dysfunctional in Alzheimer’s disease. Here, we further investigate the function of ZCCHC17. Co-immunoprecipitation of ZCCHC17 followed by mass spectrometry analysis in human iPSC-derived neurons reveals that ZCCHC17’s binding partners are enriched for RNA splicing proteins. ZCCHC17 knockdown results in widespread RNA splicing changes that significantly overlap with splicing changes found in AD brain tissue, with synaptic genes commonly affected. ZCCHC17 expression positively correlates with cognitive resilience in AD patients, and we uncover an APOE4-dependent negative correlation of ZCCHC17 expression with tangle burden. Furthermore, a majority of ZCCHC17 interactors also co-IP with known tau interactors, and we find significant overlap between alternatively spliced genes in ZCCHC17 knockdown and tau overexpression neurons. These results demonstrate ZCCHC17’s role in neuronal RNA processing and its interactions with pathology and cognitive resilience in AD.

2025-03-22 | GSE199241 | GEO

ACSS2 upregulation enhances neuronal resilience to aging and neurodegeneration [RNA-seq]

Project description:Epigenetic mechanisms, including histone acetylation, play a key role in learning and memory, with recent evidence of a role in neuronal function in Alzheimer?s disease and Related Dementia (ADRD). Acetyl-CoA synthetase 2 (ACSS2), an enzyme that generates acetyl-CoA, is central to histone acetylation and gene regulation, particularly in neurons, due to their unique metabolic demands and their postmitotic state. ACSS2 can be recruited to the nucleus and to chromatin, locally supplying acetyl-CoA to directly fuel histone acetyltransferase enzymes and key neuronal gene expression. This regulatory mechanism may be a promising target for therapeutic intervention in neurodegenerative diseases because systemic ACSS2 deletion in mice, although largely normal in physiology, is greatly impaired in memory. Here we investigated whether increasing levels of ACSS2 could protect neurons against disease and age-associated cognitive decline. Given the role of tau in ADRD, we used primary hippocampal neurons that mimic the sporadic development of tau pathology, and used the P301S transgenic mouse model for tau-induced memory decline. Our results show in these in vitro and in vivo models of tauopathy, that ACSS2 upregulation mitigates tau-induced transcriptional alterations, enhances neuronal resilience against tau pathology, improves long-term potentiation, and ameliorates memory deficits. Expanding upon these findings, we investigated deficits in aged mice, and reveal that increasing histone acetylation through ACSS2 upregulation improves age-associated memory decline. These findings indicate that increasing ACSS2 is highly effective in countering age- and tau-induced transcriptome changes, preserving elevated levels of synaptic genes, and safeguarding synaptic integrity. We thus highlight ACSS2 as a key player in the epigenetic regulation of cognitive aging and ADRD, providing a foundation for targeted therapeutics to enhance brain resilience and function.

2025-12-09 | GSE254996 | GEO

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