Modulation of histone deacetylase 2 (HDAC2) drives neuronal gene expression, mitochondrial dynamics and AD pathophysiology in human stem cell derived neurons

Abstract

Background Histone deacetylase 2 (HDAC2) is a major HDAC protein in the adult brain and has been shown to regulate many neuronal genes. Aberrant expression of HDAC2 and subsequent dysregulation of neuronal gene expression has been implicated in Alzheimer’s disease (AD) and brain aging. In vitro models of AD and other neurodegenerative disorders using human induced pluripotent stem cells (hiPSCs) are being increasingly utilized and have provided novel insights into disease mechanisms. However, the role of HDAC2 in living, human neurons and how its manipulation in an AD model may affect disease phenotypes has not been investigated. Method We used human induced pluripotent stem cells and lentiviral‐mediated manipulation of HDAC2 in hiPSC‐derived neurons to study the effects of increasing or decreasing HDAC2 expression on neuronal mitochondrial gene expression, morphology, and AD phenotypes. Result In this study, we show that levels of HDAC2 naturally decrease as hiPSCs are differentiated towards a neuronal lineage and that this suppression of HDAC2 inversely corresponds to an increase in neuronal‐specific isoforms of Endophilin‐B1, a multifunctional protein involved in mitochondrial dynamics. Manipulation of HDAC2 and Endophilin‐B1 using lentiviral approaches shows that knock‐down of HDAC2 or overexpression of Endophilin‐B1 promote mitochondrial elongation in hiPSC‐derived neurons, but HDAC2 knock‐down specifically influences genes regulating neuronal mitochondrial dynamics. We also observe that the endogenous decrease in HDAC2 levels upon neuronal differentiation also correlates with natural increases in neuronal activity and knock‐down of HDAC2 in differentiated neurons increases expression of genes related to neuronal synapses and further increases neuronal firing. Finally, we demonstrate that knock‐down of HDAC2 reduces amyloid beta peptides and the phospho/total Tau ratio in iPSC‐derived neurons. Conclusion Collectively, our study demonstrates that HDAC2 regulates key neuronal functional and bioenergetic pathways in hiPSC‐derived neurons and suggests that HDAC2 may represent a novel therapeutic target for AD.

Oxyresveratrol-β-cyclodextrin mitigates streptozotocin-induced Alzheimer's model cognitive impairment, histone deacetylase activity in rats: in silico & in vivo studies

“…Earlier, the HDAC inhibitors were used to exert anticancer efficacy 7 . However, the neuroprotection of HDAC inhibitors is accumulating in the existing literature 7 , 9 . A HDAC inhibitor, intended to serve as a multi-target drug against both HDAC and acetylcholine esterase, demonstrated potent action against Aβ-aggregation and selective inhibition of HDAC6 10 .…”

Oxyresveratrol-β-cyclodextrin mitigates intracerebral STZ-induced Alzheimer’s disease via suppression of hippocampal and cortical cognitive impairment and histone deacetylase activity in rats: In silico and In vivo studies

“…Earlier, the HDAC inhibitors were used to exert anticancer e cacy (Shukla and Tekwani 2020). However, the neuroprotection of HDAC inhibitors is accumulating in the existing literature (Frankowski et al 2020;Shukla and Tekwani 2020). Inhibitors of HDAC increase the level of histone acetylation, enhancing memory and learning, and impacting the functions of proteins crucial to Alzheimer's disease.…”