Pan Wen, Xu Long-Fei, Wang Yu-Xin, Wang Yi-Jie, Wang Jia-Qing, Qian Xin, Zhou Cheng-Zhi, Wang Hua, Fan Xiao-Hua, Wang Jia
The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China.
Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China.
FASEB J. 2025 May 15;39(9):e70582. doi: 10.1096/fj.202403299RR.
Strategies aimed at enhancing the capacity of neural stem cells (NSCs) to generate multipotential, proliferative, and migratory cell populations capable of efficient neuronal differentiation are crucial for structural repair following neurodegenerative damage. The role of Forkhead-box gene 1 (FOXG1) in pattern formation, cell proliferation, and specification has been established. However, its involvement in Alzheimer's disease (AD) remains largely unknown. Here, we investigated the association between Foxg1 gene variants and AD-like behavioral deficits, amyloid-β (Aβ) aggregate formation, as well as p21 expression. Furthermore, we explored whether targeting the FOXG1-regulated cell cycle contributes to the promotion of adult neurogenesis in the context of AD. In this study, we successfully induced overexpression of FOXG1 in the hippocampus of AD brains through adeno-associated virus-Foxg1 infusion. Activation of FOXG1 rescued spatial learning disabilities, short-term memory deficits, and sensorimotor gating impairments observed in AD transgenic animals. By inhibiting p21 WAF1/cyclin-dependent kinase interacting protein 1 (p21)-mediated cell cycle arrest, FOXG1 facilitates the activation and proliferation of NSCs. Additionally, the Foxg1 gene promotes an increase in precursor population size and enhances neuroblast differentiation. These combined effects on proliferation and differentiation lead to the generation of postmitotic neurons within the hippocampus in AD animals. Together, these findings demonstrate the importance of cooperation between FOXG1 and p21 for maintaining NSC self-renewal while facilitating neuronal lineage progression and contributing to endogenous neurogenesis during AD. Elevating levels of FOXG1 either pharmacologically or through alternative means could potentially serve as a therapeutic strategy for treating AD.
旨在增强神经干细胞（NSCs）生成能够高效神经元分化的多能、增殖和迁移细胞群体能力的策略，对于神经退行性损伤后的结构修复至关重要。叉头框基因1（FOXG1）在模式形成、细胞增殖和细胞特化中的作用已得到证实。然而，其在阿尔茨海默病（AD）中的作用仍 largely未知。在此，我们研究了Foxg1基因变体与AD样行为缺陷、淀粉样β（Aβ）聚集体形成以及p21表达之间的关联。此外，我们探讨了在AD背景下靶向FOXG1调节的细胞周期是否有助于促进成体神经发生。在本研究中，我们通过腺相关病毒-Foxg1注射成功诱导了AD脑海马中FOXG1的过表达。FOXG1的激活挽救了AD转基因动物中观察到的空间学习障碍、短期记忆缺陷和感觉运动门控损伤。通过抑制p21 WAF1/细胞周期蛋白依赖性激酶相互作用蛋白1（p21）介导的细胞周期停滞，FOXG1促进了NSCs的激活和增殖。此外，Foxg1基因促进前体细胞群体大小增加并增强神经母细胞分化。这些对增殖和分化的联合作用导致AD动物海马中产生有丝分裂后神经元。总之，这些发现证明了FOXG1和p21之间合作对于维持NSC自我更新的重要性，同时促进神经元谱系进展并在AD期间促进内源性神经发生。通过药理学或其他方式提高FOXG1水平可能潜在地作为治疗AD的策略。
