Department of Neurology, Drum Tower Hospital, Medical School and The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu 210008, PR China; Institute of Brain Sciences, Nanjing University, Nanjing, Jiangsu 210093, PR China; Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210008, PR China; Jiangsu Province Stroke Center for Diagnosis and Therapy, Nanjing, Jiangsu 210008, PR China; Nanjing Neuropsychiatry Clinic Medical Center, Nanjing, Jiangsu 210008, PR China.
Department of Neurology, Drum Tower Hospital of Nanjing Medical University, Nanjing, Jiangsu 211166, PR China.
Mol Ther. 2021 Jan 6;29(1):396-408. doi: 10.1016/j.ymthe.2020.09.006. Epub 2020 Sep 5.
Alzheimer's disease (AD) is the most common neurodegenerative disorder leading to dementia in the elderly, and the mechanisms of AD are not fully defined. MicroRNAs (miRNAs) have been shown to contribute to memory deficits in AD. In this study, we identified that miR-204-3p was downregulated in the hippocampus and plasma of 6-month-old APPswe/PS1dE9 (APP/PS1) mice. miR-204-3p overexpression attenuated memory and synaptic deficits in APP/PS1 mice. The amyloid levels and oxidative stress were decreased in the hippocampus of APP/PS1 mice after miR-204-3p overexpression. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (Nox4) was a target of miR-204-3p, and Nox4 inhibition by GLX351322 protected neuronal cells against Aβ-induced neurotoxicity. Furthermore, GLX351322 treatment rescued synaptic and memory deficits, and decreased oxidative stress and amyloid levels in the hippocampus of APP/PS1 mice. These results revealed that miR-204-3p attenuated memory deficits and oxidative stress in APP/PS1 mice by targeting Nox4, and miR-204-3p overexpression and/or Nox4 inhibition might be a potential therapeutic strategy for AD treatment.
阿尔茨海默病（AD）是导致老年人痴呆的最常见神经退行性疾病，其发病机制尚未完全阐明。研究表明 microRNAs（miRNAs）在 AD 的记忆缺陷中起作用。本研究发现 miR-204-3p 在 6 月龄 APPswe/PS1dE9（APP/PS1）小鼠海马体和血浆中表达下调。miR-204-3p 过表达可减轻 APP/PS1 小鼠的记忆和突触缺陷。miR-204-3p 过表达可降低 APP/PS1 小鼠海马体中的淀粉样蛋白水平和氧化应激。烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶 4（Nox4）是 miR-204-3p 的靶标，GLX351322 抑制 Nox4 可保护神经元细胞免受 Aβ诱导的神经毒性。此外，GLX351322 治疗可挽救 APP/PS1 小鼠的突触和记忆缺陷，降低海马体中的氧化应激和淀粉样蛋白水平。这些结果表明，miR-204-3p 通过靶向 Nox4 减轻 APP/PS1 小鼠的记忆缺陷和氧化应激，miR-204-3p 的过表达和/或 Nox4 抑制可能是 AD 治疗的潜在治疗策略。
