HDAC3 negatively regulates spatial memory in a mouse model of Alzheimer's disease

Abstract

SummaryThe accumulation and deposition of beta‐amyloid (Aβ) is a key neuropathological hallmark of Alzheimer's disease (AD). Histone deacetylases (HDACs) are promising therapeutic targets for the treatment of AD, while the specific HDAC isoforms associated with cognitive improvement are poorly understood. In this study, we investigate the role of HDAC3 in the pathogenesis of AD. Nuclear HDAC3 is significantly increased in the hippocampus of 6‐ and 9‐month‐old APPswe/PS1dE9 (APP/PS1) mice compared with that in age‐matched wild‐type C57BL/6 (B6) mice. Lentivirus ‐mediated inhibition or overexpression of HDAC3 was used in the hippocampus of APP/PS1 mice to investigate the role of HDAC3 in spatial memory, amyloid burden, dendritic spine density, glial activation and tau phosphorylation. Inhibition of HDAC3 in the hippocampus attenuates spatial memory deficits, as indicated in the Morris water maze test, and decreases amyloid plaque load and Aβ levels in the brains of APP/PS1 mice. Dendritic spine density is increased, while microglial activation is alleviated after HDAC3 inhibition in the hippocampus of 9‐month‐old APP/PS1 mice. Furthermore, HDAC3 overexpression in the hippocampus increases Aβ levels, activates microglia, and decreases dendritic spine density in 6‐month‐old APP/PS1 mice. In conclusion, our results indicate that HDAC3 negatively regulates spatial memory in APP/PS1 mice and HDAC3 inhibition might represent a potential therapy for the treatment of AD.

The HDAC3 inhibitor RGFP966 ameliorated ischemic brain damage by downregulating the AIM2 inflammasome

“…Unlike other Class I HDACs, HDAC3 contains both nuclear export signal (180-313 aa in the central portion) and the nuclear localization signal (312-428 aa in the C-terminal), 22 which indicated that HDAC3 may shuttle between the cytoplasm and nucleus by itself. In neurological diseases, the critical roles of HDAC3 in Huntington disease 1 and Alzheimer disease [26][27][28] have been well established. Emerging evidences suggested that cytoplasmic translocation of HDAC3 may be related with inflammatory molecular including IκBα 23 and STAT3.…”

“…25 Thus, accurately understanding the biological effects of specific HDACs could be beneficial to the development of more specific and well-tolerated therapeutic strategies. In neurological diseases, the critical roles of HDAC3 in Huntington disease 1 and Alzheimer disease [26][27][28] have been well established. HDAC3 was reported to participate in dopaminergic neuronal cell death 29 and embryonic neurogenesis.…”

Dexmedetomidine attenuates the toxicity of β‑amyloid on neurons and astrocytes by increasing BDNF production under the regulation of HDAC2 and HDAC5

“…Epigenetic modulations commonly occur at histones, remodeling chromatin between relatively 'open' and 'closed' forms (10). Significant decreased acetylation of histone was reported in both AD transgenic mice and postmortem human brains (11). The level of histone acetylation is regulated by acetyltransferase and histone deacetylase (HDAC).…”

“…An increase of HDAC2 was observed in the hippocampus of AD patients (12). The electrostatic interaction between positively charged histones and negatively charged DNA leads to a condensed and repressive chromatin structure (10,11). The acetylation of histones attenuates their positive charges, resulting in a reduced affinity of histones to DNA and a free chromatin for recruiting transcription factors to genes (10,11).…”

“…The electrostatic interaction between positively charged histones and negatively charged DNA leads to a condensed and repressive chromatin structure (10,11). The acetylation of histones attenuates their positive charges, resulting in a reduced affinity of histones to DNA and a free chromatin for recruiting transcription factors to genes (10,11). HDACs can remove acetyl groups from histones, which conversely produces a condensed chromatin structure and repressed gene expressions (13).…”