Department of Chemistry, Laboratory of Stem Cells & Cell Reprogramming, Dongguk University, Seoul, Republic of Korea.
J Pineal Res. 2022 Apr;72(3):e12787. doi: 10.1111/jpi.12787.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the presence of neurotoxic beta-amyloid (Aβ) in the brain. Melatonin receptors have been reported to associate with aging and AD, and their expression decreased with the progression of AD. As an alternative to AD treatment, overexpression of melatonin receptors may lead to melatonin-like effects to treat alleviate the symptoms of AD. Here, we successfully activated the type 1 melatonin receptor (Mt1) in vivo brain using a Cas9 activator as a novel AD therapeutic strategy. The Cas9 activator efficiently activated the endogenous Mt1 gene in the brain. Activation of Mt1 via Cas9 activators modulated anti-amyloidogenic and anti-inflammatory roles in 5xFAD AD mice brain. Moreover, activation of Mt1 with the CRISPR/Cas9 activator improved cognitive deficits in an AD model. These results demonstrated the therapeutic potential of melatonin receptor activation via CRISPR/Cas9 activator for AD.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，其特征是大脑中存在神经毒性β-淀粉样蛋白（Aβ）。已经有报道称褪黑素受体与衰老和 AD 有关，并且它们的表达随着 AD 的进展而降低。作为 AD 治疗的替代方法，过表达褪黑素受体可能会产生类似于褪黑素的作用，从而治疗缓解 AD 的症状。在这里，我们成功地使用 Cas9 激活剂在体内大脑中激活了 1 型褪黑素受体（Mt1），这是一种新型的 AD 治疗策略。Cas9 激活剂可有效激活大脑中的内源性 Mt1 基因。通过 Cas9 激活剂激活 Mt1 可调节 5xFAD AD 小鼠大脑中的抗淀粉样和抗炎作用。此外，使用 CRISPR/Cas9 激活剂激活 Mt1 可改善 AD 模型中的认知缺陷。这些结果表明，通过 CRISPR/Cas9 激活剂激活褪黑素受体对 AD 具有治疗潜力。
