Byline: Li-Hua. Li, Wen-Na. Peng, Yu. Deng, Jing-Jing. Li, Xiang-Rong. Tian
The histone deacetylase inhibitor, trichostatin A, is used to treat Alzheimer’s disease and can improve learning and memory but its underlying mechanism of action is unknown. To determine whether the therapeutic effect of trichostatin A on Alzheimer’s disease is associated with the nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like epichlorohydrin-related protein-1 (Keap1) signaling pathway, amyloid ß-peptide 25-35 (Aß[sub]25-35) was used to induce Alzheimer’s disease-like pathological changes in SH-SY5Y neuroblastoma cells. Cells were then treated with trichostatin A. The effects of trichostatin A on the expression of Keap1 and Nrf2 were detected by real-time quantitative polymerase chain reaction, western blot assays and immunofluorescence. Total antioxidant capacity and autophagy activity were evaluated by total antioxidant capacity assay kit and light chain 3-I/II levels, respectively. We found that trichostatin A increased cell viability and Nrf2 expression, and decreased Keap1 expression in SH-SY5Y cells. Furthermore, trichostatin A increased the expression of Nrf2-related target genes, such as superoxide dismutase, NAD(P)H quinone dehydrogenase 1 and glutathione S-transferase, thereby increasing the total antioxidant capacity of SH-SY5Y cells and inhibiting amyloid ß-peptide-induced autophagy. Knockdown of Keap1 in SH-SY5Y cells further increased trichostatin A-induced Nrf2 expression. These results indicate that the therapeutic effect of trichostatin A on Alzheimer’s disease is associated with the Keap1-Nrf2 pathway. The mechanism for this action may be that trichostatin A increases cell viability and the antioxidant capacity of SH-SY5Y cells by alleviating Keap1-mediated inhibition Nrf2 signaling, thereby alleviating amyloid ß-peptide-induced cell damage.
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by memory impairment and behavioral disorders (Dodich et al., 2016; Lin et al., 2018; Mokhtar et al., 2018; Zhang et al., 2019), and is pathologically characterized by the presence of extracellular amyloid plaques, intracellular neurofibrillary tangles, and synapse loss (Hong et al., 2016; Zhao, 2016; Filadi and Pizzo, 2019). Understanding the mechanism of AD is crucial for preventing and treating the disease. Mutations in amyloid precursor protein are associated with increased production of amyloid ß-peptide (Aß) (Waring and Rosenberg, 2008; Selkoe and Hardy, 2016). Aß disturbs neuronal metabolism (Kuhla et al., 2004; Campos-Pena et al., 2017) and Aß in senile plaques can amplify microglial activation by a coexisting submaximal inflammatory stimulus (Verbeeck et al., 2017). Aß-mediated oxidative stress is considered to cause neuronal damage and to be a major factor in AD pathogenesis (Hardy and Selkoe, 2002; Shioi et al., 2007; Jiang et al., 2016). It is well documented that Aß induces some of the symptoms of AD (Selkoe, 1994; Hardy and Selkoe, 2002; Wang and Liu, 2012; Bruggink et al., 2013; Tönnies and Trushina, 2017). Aß protein fragment 25-35 (Aß[sub]25-35) is widely used to establish in vitro cell models of AD (Kaminsky et al., 2010; Wang and Liu, 2012; Chang and Teng, 2015). Recent therapeutic research has focused on developing amyloid plaque-specific antibodies and antioxidants to protect against Aß-mediated oxidative stress (Hardy and Selkoe, 2002; Youn et al., 2014).
The Kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid...