ACSS2 and the metabolic‐epigenetic axis in Alzheimer’s disease

Abstract

AbstractBackgroundWe examine the contribution of the metabolic‐epigenetic regulatory axis1to protective histone acetylation in the brain, which is impaired in Alzheimer’s disease (AD). ACSS2 (acetyl‐CoA synthetase 2) is a key metabolic enzyme that is chromatin‐bound in neurons2. ACSS2 is recruited to specific promoters and maintains a local pool of acetyl‐CoA that fuels histone acetylation and drives the expression of key neuronal genes that regulate learning and memory.MethodWe characterize the genomic distribution of neuronal histone acetylation and ACSS2 in post‐mortem human brains from young, old and AD subjects. We also assess dynamic changes in chromatin localization and function of neuronal ACSS2 in mouse models of AD that rely on intra‐cerebral injection of human pathological AD‐tau in non‐transgenic mice3. To further establish the role of ACSS2 in AD etiology, we perform AD‐tau injections in mice lacking or overexpressing ACSS2 and assess consequent changes in AD neuropathology and phenotype.ResultWe showed that ACSS2 is required for brain histone acetylation as well as learning and memory in vivo 4. Intriguingly, we recently showed that loss of protective histone acetylation potentially underlies AD and related dementia in humans5. In post‐mortem human brains from young, old and AD subjects, we found that while normal aging is characterized by increased neuronal histone acetylation, this enrichment is lost in AD. We thus hypothesize that impaired function of ACSS2 could underlie the loss of protective histone acetylation in AD and consequent neuropathological and cognitive impairments. We anticipate that chromatin‐bound ACSS2 is lost during the development of AD and that this loss underlies subsequent changes in histone acetylation, chromatin accessibility and transcription of key neuronal genes required for learning and memory. We expect a more severe disease phenotype in ACSS2 knock‐out mice while ACSS2 overexpression might have a protective effect.ConclusionOverall, we expect this study to be of significant interest to the field as positive results could establish ACSS2 as a key neuroprotective metabolic enzyme and a potential new therapeutic target for humans suffering from AD. Acknowledgements: G.E. is supported by the Alzheimer’s Association Research Fellowship (AARF‐19‐618159).