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bioRxiv · 10.1101/2024.04.08.588604

ACSS2 contributes to transcriptional regulation in Cajal-Retzius cells in a mouse model of Alzheimer's disease

Egervari, G.·Alexander, D. C.·Donahue, G.·Huang, H.·Hogan, C.·Mendoza, M.·Garcia, B. A.·Bonini, N. M.·Berger, S. L.
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Abstract

Dysregulation of histone acetylation in the brain has emerged as a major contributor to human Alzheimers disease (AD). The mechanisms by which these 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 chromatin-associated in neurons. ACSS2 is recruited to specific promoters and generates a local pool of acetyl-CoA from acetate, thereby fueling histone acetylation and driving the expression of neuronal genes that regulate learning and memory. Here, we examine the contribution of ACSS2-mediated histone acetylation to AD-related molecular and behavioral outcomes. 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. Further, we identify Cajal-Retzius neurons as a critical hippocampal neuronal population affected, exhibiting the largest epigenetic and transcriptional dysregulation. Overall, these results reveal ACSS2 as a key neuroprotective metabolic enzyme, dysregulation of which might play an important role in the etiology of human AD, and guide the development of future therapies for AD and related dementia.

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Egervari, G., Alexander, D. C., Donahue, G., Huang, H., Hogan, C., Mendoza, M., Garcia, B. A., Bonini, N. M., Berger, S. L.. 2024-04-12. ACSS2 contributes to transcriptional regulation in Cajal-Retzius cells in a mouse model of Alzheimer's disease. https://doi.org/10.1101/2024.04.08.588604

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