School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China.
The Brain Cognition and Brain Disease Institute (BCBDI), CAS Key Laboratory of Brain Connectome and Manipulation, Faculty of Pharmaceutical Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China.
CNS Neurosci Ther. 2023 Jul;29(7):1848-1864. doi: 10.1111/cns.14143. Epub 2023 Mar 7.
Alzheimer's disease (AD) is characterized by the abnormal accumulation of hyperphosphorylated tau proteins and amyloid-beta (Aβ) peptides. Recent studies have shown that many microRNAs (miRNAs) are dysregulated in AD, and modulation of these miRNAs can influence the development of tau and Aβ pathology. The brain-specific miRNA miR-128, encoded by MIR128-1 and MIR128-2, is important for brain development and dysregulated in AD. In this study, the role of miR-128 in tau and Aβ pathology as well as the regulatory mechanism underlying its dysregulation were investigated.
The effect of miR-128 on tau phosphorylation and Aβ accumulation was examined in AD cellular models through miR-128 overexpression and inhibition. The therapeutic potential of miR-128 in AD mouse model was assessed by comparing phenotypes of 5XFAD mice administered with miR-128-expressing AAVs with 5XFAD mice administered with control AAVs. Phenotypes examined included behavior, plaque load, and protein expression. The regulatory factor of miR-128 transcription was identified through luciferase reporter assay and validated by siRNA knockdown and ChIP analysis.
Both gain-of-function and loss-of-function studies in AD cellular models reveal that miR-128 represses tau phosphorylation and Aβ secretion. Subsequent investigations show that miR-128 directly inhibits the expression of tau phosphorylation kinase GSK3β and Aβ modulators APPBP2 and mTOR. Upregulation of miR-128 in the hippocampus of 5XFAD mice ameliorates learning and memory impairments, decreases plaque deposition, and enhances autophagic flux. We further demonstrated that C/EBPα transactivates MIR128-1 transcription, while both C/EBPα and miR-128 expression are inhibited by Aβ.
Our findings suggest that miR-128 suppresses AD pathogenesis, and could be a promising therapeutic target for AD. We also find a possible mechanism underlying the dysregulation of miR-128 in AD, in which Aβ reduces miR-128 expression by inhibiting C/EBPα.
阿尔茨海默病（AD）的特征是异常积累过度磷酸化的 tau 蛋白和淀粉样β（Aβ）肽。最近的研究表明，许多 microRNAs（miRNAs）在 AD 中失调，调节这些 miRNAs 可以影响 tau 和 Aβ 病理学的发展。大脑特异性 miRNA miR-128，由 MIR128-1 和 MIR128-2 编码，对大脑发育很重要，在 AD 中失调。在这项研究中，研究了 miR-128 在 tau 和 Aβ 病理学中的作用以及其失调的调节机制。
通过 miR-128 过表达和抑制，在 AD 细胞模型中研究了 miR-128 对 tau 磷酸化和 Aβ 积累的影响。通过比较给予 miR-128 表达 AAV 的 5XFAD 小鼠与给予对照 AAV 的 5XFAD 小鼠的表型，评估了 miR-128 在 AD 小鼠模型中的治疗潜力。检查的表型包括行为、斑块负荷和蛋白表达。通过荧光素酶报告测定鉴定 miR-128 转录的调节因子，并通过 siRNA 敲低和 ChIP 分析进行验证。
AD 细胞模型中的功能获得和功能丧失研究均表明，miR-128 抑制 tau 磷酸化和 Aβ 分泌。随后的研究表明，miR-128 直接抑制 tau 磷酸化激酶 GSK3β 和 Aβ 调节剂 APPBP2 和 mTOR 的表达。5XFAD 小鼠海马中 miR-128 的上调改善了学习和记忆障碍，减少了斑块沉积，并增强了自噬通量。我们进一步证明，C/EBPα 反式激活 MIR128-1 转录，而 C/EBPα 和 miR-128 的表达均受 Aβ 抑制。
我们的研究结果表明，miR-128 抑制 AD 发病机制，可能是 AD 的有前途的治疗靶点。我们还发现了 AD 中 miR-128 失调的潜在机制，其中 Aβ 通过抑制 C/EBPα 降低 miR-128 的表达。
