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

(2023) 18:47 Lin et al. Molecular Neurodegeneration https://doi.org/10.1186/s13024-023-00625-4 Molecular Neurodegeneration RESEARCH ARTICLE Open Access ACSS2‑dependent histone acetylation improves cognition in mouse model of Alzheimer’s disease Yingbin Lin1,2†, Anlan Lin3†, Lili Cai1†, Weibin Huang1,2, Shanzhi Yan1, Yuanxiang Wei3, Xinglin Ruan1, Wenting Fang1, Xiaoman Dai1, Jinbo Cheng4, Jie Zhang1, Wanjin Chen2, Qinyong Ye1, Xiaochun Chen1* and Jing Zhang1*    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 ACSS2mediated 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. Keywords Alzheimer’s disease, ACSS2, Synaptic plasticity, Histone acetylation, Acetate, Glutamate receptors † Yingbin Lin, Anlan Lin and Lili Cai are authors contributed equally to this work. *Correspondence: Xiaochun Chen ; Jing Zhang ; Full list of author information is available at the end of the article © The Author(s) 2023. 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The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Lin et al. Molecular Neurodegeneration (2023) 18:47 Page 2 of 21 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. Background As the most common type of dementia, Alzheimer’s disease (AD) is undoubtedly one of the most burdensome diseases of the twenty-first century [1]. In its pathogenesis, the disease has taken an insidious course, with amyloid-β (Aβ), essential for AD diagnosis, accumulating at least 20 years prior to the onset of any observable symptoms [2]. Therefore, in addition to early diagnosis and early intervention, it is of great urgency and significance to explore effective treatments for patients with mid-to-late AD [3]. During the long interval between Aβ accumulation and appearance of noticeable symptoms, in addition to tau pathology [4] and glia reaction [5], the impairment of synaptic plasticity [6–8] and loss of synapses [7–10] are the crucial factors for clinical AD progression from the pre-symptomatic stage to mild cognitive impairment (MCI) to dementia. Therefore, an exploration of the potential underlying mechanisms that can be exploited to restore the impaired synaptic plasticity in AD brain holds great promises for AD treatment. Epigenetic regulation and chromatin remodeling have been reported to participate in the regulation of numerous neuronal functions, ranging from synaptic plasticity to learning and memory [11–16]. As a kind of chromatin remodeling, histone acetylation weakens the electrostatic affinity between histones and DNA, thus promoting the fundamental gene transcription for long-term synaptic plasticity and memory [17–21]. In the hippocampus of normal aging mice, histones H2B/H4 failed to be acetylated during learning, rendering them incapable of initiating the expression of memory consolidation-related genes [22, 23]. In the brain of APP/PS1 transgenic mice (a mouse model of AD), the acetylation of histone H3 [24] and H4 [25] is significantly downregulated. Similar findings have been reported in the postmortem brain tissues from AD patients [26, 27]. Several recent studies have proposed modifying histone acetylation as a promising Lin et al. Molecular Neurodegeneration (2023) 18:47 therapeutic strategy for AD [25, 28]. However, due to specificity, efficacy, and safety issues, the insights gleaned from classic AD animal models have rarely been translated into practical clinical trials, despite the capability of histone-deacetylase (HDACs) inhibitors to ameliorate cognitive impairment [29, 30]. Thus, an alternative exploration into histone acetylation, such as a probe into the source of acetyl donor, may provide a better candidate for the restoration of synaptic plasticity in AD treatment. As the acetyl donor, acetyl coenzyme A (acetyl-CoA), generated by the metabolic enzymes (...truncated)