Beneficial Effects of Sulforaphane Treatment in Alzheimer's Disease May Be Mediated through Reduced HDAC1/3 and Increased P75NTR Expression.

Jingzhu Zhang,Fuyuan Zhou,Rui Zhang,Congmin Jiang,Li An,Zhipeng Zhan,Aiping Xing,Xinhui Li,Yanqiu Chen

doi:10.3389/fnagi.2017.00121

Abstract

Alzheimer's disease is an irreversible, progressive neurodegenerative disorder. The accumulation of Aβ in the brain is thought to play a causative role in the development of cognitive dysfunction in Alzheimer's disease. The p75 neurotrophin receptor is of great importance to protect against the Aβ burden and its expression is regulated by histone acetylation. This study investigated whether the phytochemical sulforaphane, a pan-histone deacetylase inhibitor, up-regulates the p75 neurotrophin receptor expression via affecting histone acetylation in protection against Alzheimer's disease. We found that sulforaphane ameliorated behavioral cognitive impairments and attenuated brain Aβ burden in Alzheimer's disease model mice. Additionally, sulforaphane reduced the expression of histone deacetylase1, 2, and 3, up-regulated p75 neurotrophin receptor, and increased levels of acetylated histone 3 lysine 9 and acetylated histone 4 lysine 12 in the cerebral cortex of Alzheimer's disease model mice as well as in Aβ-exposed SH-SY5Y cells. Furthermore, silencing of histone deacetylase1 and 3, but not histone deacetylase2, gene expression with small interfering RNA caused up-regulation of p75 neurotrophin receptor in SH-SY5Y cells. In conclusion, this study demonstrates that sulforaphane can ameliorate neurobehavioral deficits and reduce the Aβ burden in Alzheimer's disease model mice, and the mechanism underlying these effects may be associated with up-regulation of p75 neurotrophin receptor mediated, apparently at least in part, via reducing the expression of histone deacetylase1 and 3.

Highlights

Alzheimer’s disease (AD) is an irreversible, progressive neurodegenerative disorder that affects more than 46 million people worldwide (Prince, 2015)
We found that the beneficial effects of SFN treatment in AD may be associated with up-regulation of p75 neurotrophin receptor (p75NTR) expression, which is mediated, at least partly, by SFNinduced reduction of HDAC1 and HDAC3 expression
We found that expression of p75NTR mRNA and protein was increased in HDAC1 (Figures 12A–C) or HDAC3 (Figures 12G–I) knockdown cells compared with p75NTR levels in controls (p < 0.05)

Summary

Introduction

Alzheimer’s disease (AD) is an irreversible, progressive neurodegenerative disorder that affects more than 46 million people worldwide (Prince, 2015). Recent memory impairment is the earliest notable symptom of patients with AD, and this symptom progresses gradually into severe dementia, characterized by impairments in learning, memory retrieval, reasoning, communication, and one’s ability to carry out daily activities (Chin-Chan et al, 2015). AD is characterized by SFN Regulates p75NTR by HDACs extracellular deposition of amyloid-beta (Aβ) protein combined with formation of senile plaques, intracellular neurofibrillary tangles (NFTs), and the death of cholinergic neurons (Attems et al, 2012). The “Aβ cascade hypothesis” postulates that the fundamental pathogenetic mechanism responsible for neuronal degenerative changes and the compromise of cognitive functions in AD is an excessive accumulation of Aβ in the brain (Hardy and Selkoe, 2002). Reducing the brain Aβ burden has become a key strategy in AD therapy and prevention

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