Department of Neurology, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, 60 Fenwood Rd, 9006, Boston, MA, 02115, USA.
Department of Psychiatry, McLean Hospital and Harvard Medical School, Belmont, MA, 02478, USA.
Acta Neuropathol. 2018 Oct;136(4):537-555. doi: 10.1007/s00401-018-1880-5. Epub 2018 Jul 7.
MicroRNAs (miRNA) regulate fundamental biological processes, including neuronal plasticity, stress response, and survival. Here, we describe a neuroprotective function of miR-132, the miRNA most significantly downregulated in neurons in Alzheimer's disease. We demonstrate that miR-132 protects primary mouse and human wild-type neurons and more vulnerable Tau-mutant neurons against amyloid β-peptide (Aβ) and glutamate excitotoxicity. It lowers the levels of total, phosphorylated, acetylated, and cleaved forms of Tau implicated in tauopathies, promotes neurite elongation and branching, and reduces neuronal death. Similarly, miR-132 attenuates PHF-Tau pathology and neurodegeneration, and enhances long-term potentiation in the P301S Tau transgenic mice. The neuroprotective effects are mediated by direct regulation of the Tau modifiers acetyltransferase EP300, kinase GSK3β, RNA-binding protein Rbfox1, and proteases Calpain 2 and Caspases 3/7. These data suggest miR-132 as a master regulator of neuronal health and indicate that miR-132 supplementation could be of therapeutic benefit for the treatment of Tau-associated neurodegenerative disorders.
微小 RNA（miRNA）调节基本的生物学过程，包括神经元可塑性、应激反应和存活。在这里，我们描述了 miR-132 的神经保护功能，miR-132 是阿尔茨海默病神经元中下调最显著的 miRNA。我们证明 miR-132 可保护原代小鼠和人类野生型神经元以及更脆弱的 Tau 突变神经元免受淀粉样 β 肽（Aβ）和谷氨酸兴奋性毒性的侵害。它降低了与 tau 病相关的 Tau 的总、磷酸化、乙酰化和切割形式的水平，促进了神经突的伸长和分支，并减少了神经元死亡。同样，miR-132 减轻了 PHF-Tau 病理学和神经退行性变，并增强了 P301S Tau 转基因小鼠的长时程增强作用。神经保护作用是通过直接调节 Tau 修饰物乙酰转移酶 EP300、激酶 GSK3β、RNA 结合蛋白 Rbfox1 以及蛋白酶钙蛋白酶 2 和 Caspases 3/7 来介导的。这些数据表明 miR-132 是神经元健康的主要调节剂，并表明 miR-132 的补充可能对治疗 Tau 相关神经退行性疾病具有治疗益处。
