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

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. Overall design: Contains RNA-seq data obtained from male and female mice (dissected dorsal hippocampus) treated intracranially with either PBS or purified tau protein from human AD patient brains. Mice have either WT or ACSS2KO genetic background. The purpose of the study is to examine the interaction between the ACSS2 absence and the presence of pathological Tau, with a focus on memory. Six study groups are provided: male-PBS-WT, male-PBS-KO, male-Tau-WT, male-Tau-KO, female-Tau-WT, and female-Tau-KO; note that we do not have PBS-treated females) with three biological replicates each except for female-Tau-WT which has two. For purposes of downstream analysis, only the male samples were used.