There is a compelling need to develop disease-modifying therapies for Alzheimer’s disease (AD), the most common neuro-degenerative disorder. Together with recent progress in vector development for efficiently targeting the central nervous system, gene therapy has been suggested as a potential therapeutic modality to overcome the limited delivery of conventional types of drugs to and within the damaged brain. In addition, given increasing evidence of the strong link between glia and AD pathophysiology, therapeutic targets have been moving toward those addressing glial cell pathology. Nurr1 and Foxa2 are transcription/epigenetic regulators that have been reported to cooperatively regulate inflammatory and neurotrophic response in glial cells. In this study, we tested the therapeutic potential of Nurr1 and Foxa2 gene delivery to treat AD symptoms and pathologies. A series of functional, histologic, and transcriptome analyses revealed that the combined expression of Nurr1 and Foxa2 substantially ameliorated AD-associated amyloid β and Tau proteinopathy, cell senescence, synaptic loss, and neuro-inflammation in multiple in vitro and in vivo AD models. Intra-cranial delivery of Nurr1 and Foxa2 genes using adeno-associated virus (AAV) serotype 9 improved the memory and cognitive function of AD model mice. The therapeutic benefits of gene delivery were attained mainly by correcting pathologic glial function. These findings collectively indicate that AAV9-mediated Nurr1 and Foxa2 gene transfer could be an effective disease-modifying therapy for AD.

迫切需要开发针对阿尔茨海默病（AD）这种最常见的神经退行性疾病的疾病缓解疗法。结合最近在有效靶向中枢神经系统的载体开发方面取得的进展，基因疗法被认为是一种潜在的治疗方式，以克服传统类型药物向受损大脑和在受损大脑内的有限递送。此外，鉴于越来越多的证据表明神经胶质细胞与 AD 病理生理学之间存在密切联系，治疗目标已转向解决神经胶质细胞病理学问题。 Nurr1 和 Foxa2 是转录/表观遗传调节因子，据报道可以协同调节神经胶质细胞中的炎症和神经营养反应。在这项研究中，我们测试了 Nurr1 和 Foxa2 基因递送治疗 AD 症状和病理的治疗潜力。一系列功能、组织学和转录组分析表明，在多种体外和体内 AD 模型中，Nurr1 和 Foxa2 的联合表达可显着改善 AD 相关的淀粉样蛋白 β 和 Tau 蛋白病、细胞衰老、突触损失和神经炎症。使用腺相关病毒（AAV）血清型 9 颅内递送 Nurr1 和 Foxa2 基因可改善 AD 模型小鼠的记忆和认知功能。基因递送的治疗效果主要是通过纠正病理性神经胶质功能来实现的。这些发现共同表明 AAV9 介导的 Nurr1 和 Foxa2 基因转移可能是治疗 AD 的有效疾病缓解疗法。