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

  • Mol Neurodegener. 2023 Jul 12;18(1):47. doi: 10.1186/s13024-023-00625-4.
Yingbin Lin  #  1  2 ,  Anlan Lin  #  3 ,  Lili Cai  #  1 ,  Weibin Huang  1  2 ,  Shanzhi Yan  1 ,  Yuanxiang Wei  3 ,  Xinglin Ruan  1 ,  Wenting Fang  1 ,  Xiaoman Dai  1 ,  Jinbo Cheng  4 ,  Jie Zhang  1 ,  Wanjin Chen  2 ,  Qinyong Ye  1 ,  Xiaochun Chen  5 ,  Jing Zhang  6
Affiliations
  • 1. Department of Neurology, Fujian Medical University Union Hospital, Fujian Key Laboratory of Molecular Neurology and Institute of Neuroscience, Fujian Medical University, Fuzhou, China.
  • 2. Department of Neurology and Neurosurgery, Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
  • 3. The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.
  • 4. Beijing Institute of Basic Medical Sciences, Beijing, China.
  • 5. Department of Neurology, Fujian Medical University Union Hospital, Fujian Key Laboratory of Molecular Neurology and Institute of Neuroscience, Fujian Medical University, Fuzhou, China. [email protected].
  • 6. Department of Neurology, Fujian Medical University Union Hospital, Fujian Key Laboratory of Molecular Neurology and Institute of Neuroscience, Fujian Medical University, Fuzhou, China. [email protected].
  • # Contributed equally.
PMID: 37438762 DOI: 10.1186/s13024-023-00625-4
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. 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.

Keywords
ACSS2; Acetate; Alzheimer’s disease; Glutamate receptors; Histone acetylation; Synaptic plasticity.
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