Multiomic single nuclei profiling of a mouse model of Alzheimer’s disease reveals that ACSS2 confers neuronal resilience to tauopathy
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE294332 | GEO | 2026/02/20
REPOSITORIES: GEO
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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
Project description: Not available
| S-EPMC10622498 | biostudies-literature
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
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 | GSE254820 | GEO
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
Project description:Proteomics on sarkosyl-insoluble proteome of APP/PS1 and human AD brain.
2019-11-06 | PXD009306 | Pride
Project description:The degenerative process in Parkinson’s disease (PD) causes a progressive loss of dopaminergic neurons (DaNs) in the nigrostriatal system. Resolving the differences in neuronal susceptibility warrants an amenable PD model that, in comparison to post-mortem human specimens, controls for environmental and genetic differences in PD pathogenesis. At present study, we generated a primate model of PD by carotid artery injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine MPTP and sampled substantia nigra and putamen of macaque for single cell sequencing analysis.
2023-11-19 | E-MTAB-13437 | biostudies-arrayexpress
Project description:During early ischemic brain injury, glutamate receptor hyperactivation mediates neuronal death via osmotic cell swelling. Here we show that ischemia and excess NMDA receptor activation cause actin to rapidly and extensively reorganize within the somatodendritic compartment. Normally, F-actin is concentrated within dendritic spines. However, <5 min after bath-applied NMDA, F-actin depolymerizes within spines and polymerizes into stable filaments within the dendrite shaft and soma. A similar actinification occurs after experimental ischemia in culture, and photothrombotic stroke in mouse. Following transient NMDA incubation, actinification spontaneously reverses. Na+, Cl-, water, and Ca2+ influx, and spine F-actin depolymerization are all necessary, but not individually sufficient, for actinification, but combined they induce activation of the F-actin polymerization factor inverted formin-2 (INF2). Silencing of INF2 renders neurons vulnerable to cell death and INF2 overexpression is protective. Ischemia-induced dendritic actin reorganization is therefore an intrinsic pro-survival response that protects neurons from death induced by cell edema.
| S-EPMC9558009 | biostudies-literature
Project description:Alzheimer's disease (AD) is a devastating neurodegenerative disease causing irreversible cognitive decline in the elderly. There is no disease-modifying therapy for this condition and the mechanisms underpinning neuronal dysfunction and neurodegeneration are unclear. Compromised cytoskeletal integrity within neurons is reported in AD. This is believed to result from loss-of-function of the microtubule-associated protein tau, which becomes hyper-phosphorylated and deposits into neurofibrillary tangles in AD. We have developed a Drosophila model of tauopathy in which abnormal human tau mediates neuronal dysfunction characterised by microtubule destabilisation, axonal transport disruption, synaptic defects and behavioural impairments. Here we show that a microtubule-stabilising drug, NAPVSIPQ (NAP), prevents as well as reverses these phenotypes even after they have become established. Moreover, it does not alter abnormal tau levels indicating that it by-passes toxic tau altogether. Thus, microtubule stabilisation is a disease-modifying therapeutic strategy protecting against tau-mediated neuronal dysfunction, which holds great promise for tauopathies like AD.
| S-EPMC3690421 | biostudies-literature
Project description:The intracerebral spread of tau is a critical mechanism associated with functional decline in Alzheimer's disease (AD) and other tauopathies. Recently, a hypothesis has emerged suggesting that tau propagation is linked to functional neuronal connections, specifically driven by neuronal hyperactivity. However, experimental validation of this hypothesis remains limited. In this study, we investigated how tau propagation from the entorhinal cortex to the hippocampus, the neuronal circuit most susceptible to tau pathology in AD, is affected by the selective stimulation of neuronal activity along this circuit. Using a mouse model of seed-induced propagation combined with optogenetics, we found that the chronic stimulation of this neuronal connection over a 4-week period resulted in a significant increase in insoluble tau accumulation in both the entorhinal cortex and hippocampus. Importantly, the ratio of tau accumulation in the hippocampus relative to that in the entorhinal cortex, serving as an indicator of transcellular spreading, was significantly higher in mice subjected to chronic stimulation. These results support the notion that abnormal neuronal activity promotes tau propagation, thereby implicating it in the progression of tauopathy.
| S-EPMC11354494 | biostudies-literature