ACSS2 upregulation enhances neuronal resilience to aging and tau-associated neurodegeneration

ABSTRACT Epigenetic mechanisms, including histone acetylation, are pivotal for learning and memory, with 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 postmitotic state. ACSS2 can be recruited to the nucleus and 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. Previously we showed that systemic ACSS2 deletion in mice, although largely normal in physiology, is greatly impaired in memory. Here we investigated whether increasing ACSS2 levels 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 the P301S transgenic mouse model for tau-induced memory decline. Our results show 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 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. Summary ACSS2 upregulation protects neurons from disease and age-related decline by enhancing synaptic and longevity gene expression.