ACSS2-dependent histone acetylation improves cognition in mouse model of Alzheimer’s disease

Abstract

Background Nuclear acetyl-CoA pools govern histone acetylation that controls synaptic plasticity and contributes to cognitive deterioration in patients with Alzheimer’s disease (AD). Nuclear acetyl-CoA pools are generated partially from local acetate that is metabolized by acetyl-CoA synthetase 2 (ACSS2). However, the underlying mechanism of histone acetylation dysregulation in AD remains poorly understood. Methods We detected ACSS2 expression and histone acetylation levels in the brains of AD patients and 5 × FAD mice. When we altered ACSS2 expression by injecting adeno-associated virus into the dorsal hippocampus of 5 × FAD mice and replenished ACSS2 substrate (acetate), we observed changes in cognitive function by Morris water maze. We next performed RNA-seq, ChIP-qPCR, and electrophysiology to study molecular mechanism underlying ACSS2-mediated spatial learning and memory in 5 × FAD mice. Results We reported that ACSS2 expression and histone acetylation (H3K9, H4K12) were reduced in the hippocampus and prefrontal cortex of 5 × FAD mice. Reduced ACSS2 levels were also observed in the temporal cortex of AD patients. 5 × FAD mice exhibited a low enrichment of acetylated histones on the promoters of NMDARs and AMPARs, together with impaired basal and activity-dependent synaptic plasticity, all of which were rescued by ACSS2 upregulation. Moreover, acetate replenishment enhanced ac-H3K9 and ac-H4K12 in 5 × FAD mice, leading to an increase of NMDARs and AMPARs and a restoration of synaptic plasticity and cognitive function in an ACSS2-dependent manner. Conclusion ACSS2 is a key molecular switch of cognitive impairment and that targeting ACSS2 or acetate administration may serve as a novel therapeutic strategy for the treatment of intermediate or advanced AD. Graphical Abstract Nuclear acetyl-CoA pools are generated partly from local acetate that is metabolized by acetyl-CoA synthetase 2 (ACSS2). Model depicts that ACSS2 expression is downregulated in the brains of 5×FAD model mice and AD patients. Of note, ACSS2 downregulation mediates a reduction in ionotropic glutamate receptor expression through histone acetylation, which exacerbates synaptic plasticity impairment in AD. These deficits can be rescued by ACSS2 upregulation or acetate supplementation (GTA, an FDA-approved food additive), which may serve as a promising therapeutic strategy for AD treatment.

Gut microbiota regulates hepatic ischemia–reperfusion injury‐induced cognitive dysfunction via the HDAC2‐ACSS2 axis in mice

“…Histone post‐translational modifications include methylation, phosphorylation, ubiquitination, etc 23,24 . Cognitive function has been found to have a strong connection with histone acetylation/deacetylation, as demonstrated by previous studies 25,26 . Histone deacetylase 2 (HDAC2) and acetyl‐CoA synthetase 2 (ACSS2) are key enzymes that regulate this balance.…”

“…23,24 Cognitive function has been found to have a strong connection with histone acetylation/deacetylation, as demonstrated by previous studies. 25,26 Histone deacetylase 2 (HDAC2) and acetyl-CoA synthetase 2 (ACSS2) are key enzymes that regulate this balance. ACSS2 uses acetate as a substrate to synthesize Acetyl-CoA, directly promoting histone acetylation, which has an impact on learning and memory.…”

Histone acetylation in an Alzheimer’s disease cell model promotes homeostatic amyloid-reducing pathways

“…We and others have reported differential H3K27ac in human brain tissue that is dependent on the brain region surveyed: H3K27ac increases in the lateral temporal lobe 14 , but decreases in the entorhinal cortex of AD patient brains 15 . We also examined the histone acetylation mark H4K16ac and discovered a decrease in the brains of AD patients 9 , and studies in fly models of AD suggest a protective role of H4K16ac against AD pathology-related insults 65,66 Additionally, in a mouse model of AD, the histone deacetylase HDAC2 increases and H4K12ac decreases 67 , and an ameliorative effect was demonstrated in an AD mouse model of increasing acetyl-CoA synthetase 2 (ACSS2) 68 , which generates acetyl-coA and regulates histone acetylation in rodent hippocampus to promote memory 69,70 . These findings fuel speculation that histone deacetylase inhibitors could be potential therapeutics in Alzheimer's disease and other neurodegenerative diseases, to overcome a disease-associated "epigenomic blockade" 67,71 .…”

ApoE4 exacerbates the senescence of hippocampal neurons and spatial cognitive impairment by downregulating acetyl‐CoA level

“…Meanwhile, Ac-CoA pools are partially regulated by Ac-CoA synthetase 2 (ACSS2), which is essential for hippocampal spatial memory in adult mice (Mews et al, 2017). Our recent research also indicates the critical role of ACSS2 in cognitive decline in AD mice (Lin et al, 2023).…”