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

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.

As a Histone Deacetylase Inhibitor, γ‐Aminobutyric Acid Upregulates GluR2 Expression: An In Vitro and In Vivo Study

“…The same methodology was used as the one employed in a previous study to culture Human neuroblastoma SH‐SY5Y cells (Chinese Academy of Sciences cell bank, KCB2006107 YJ, Kunming, China). Mouse 3T3‐L1 preadipocytes were generously provided by professor Jingbo Pi (School of Public Health, China Medical University).…”

“…Additionally, 30 mg of thawed mouse cerebral cortex was prepared for HDAC1, HDAC2, HDAC3, and GluR2 mRNA analyses by qRT‐PCR. The same methodology was used as the one employed in a previous study to perform qRT‐PCR. In brief, total mRNA was isolated from cells or thawed cerebral cortex with an SV Total RNA Isolation System kit (CwBio, Inc., Beijing, China).…”

“…Cell treatment and sample collection procedures were performed as described for the qRT‐PCR assays. The same methodology was used as the one employed in a previous study to perform Western blots. Briefly, collected cells and thawed cerebral cortex samples were homogenized in RIPA buffer containing 0.1% protease inhibitor (Amerso, USA).…”

“…HDAC1, HDAC2, and HDAC3 small interfering RNA (siRNA) duplexes (RIBOBIO CO, LTD, Guangzhou) were used to interfere with endogenous HDAC1, HDAC2, and HDAC3 mRNA levels, respectively. The same methodology was used as the one employed in a previous study to do SiRNA. There were no significant differences in HDAC1, 2, and 3 expression levels between the untreated cells and those treated with nonspecific siRNA (scrambled siRNA, RIBOBIO CO, LTD, Guangzhou, China) in the authors' previous study.…”

Modulation the Neuro-toxicity Induced by Aluminum Chloride in Rats Using Beetroots and Broccli Extracts

“…Rivastigmine previously showed to be beneficial in preventing neuronal degeneration by increasing regional cerebral blood flow in animal model [52].…”