Jiang Hangyuan, Qi Hengxing, Tang Anying, Hu Shaohua, Lai Jianbo
Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310058, China; Edinburgh Medical School: Biomedical Sciences, College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh, UK.
Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Zhejiang Key Laboratory of Precision Psychiatry, Hangzhou 310003, China; Nanhu Brain-computer Interface Institute, Hangzhou 311100, China; Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou 311121, China.
Ageing Res Rev. 2025 Aug;110:102808. doi: 10.1016/j.arr.2025.102808. Epub 2025 Jun 17.
The decline of adult neurogenesis and neuronal function during aging underlies the onset and progression of neurodegenerative diseases such as Alzheimer's disease. Conventional therapies, including neurotransmitter modulators and antibodies targeting pathogenic proteins, offer only symptomatic improvement. As the most abundant glial cells in the brain, astrocytes outnumber neurons nearly fivefold. However, their proliferative and transdifferentiation potential renders them ideal candidates for in situ neuronal replacement. Direct astrocyte-to-neuron reprogramming offers a promising regenerative approach to restore damaged neural circuits. Herein, we propose a "car start-up" model to conceptualize this process, emphasizing the need to inhibit non-neuronal fate pathways (release the handbrake), suppress transcriptional repressors (release the footbrake), and activate neuron-specific gene expression (step on the gas). Additionally, overcoming metabolic barriers in the cytoplasm is essential for successful lineage conversion. Viral or non-viral vectors deliver reprogramming factors, while small molecules serve as metabolic and epigenetic fuel to boost efficiency. In summary, we review the current evidence supporting direct astrocyte-to-neuron reprogramming as a viable regenerative strategy in the aging brain. We also highlight the conceptual "car start-up" model as a useful framework to dissect the molecular logic of lineage conversion and emphasize its promising therapeutic potential for combating neurodegenerative diseases.
衰老过程中成人神经发生和神经元功能的衰退是诸如阿尔茨海默病等神经退行性疾病发病和进展的基础。包括神经递质调节剂和靶向致病蛋白的抗体在内的传统疗法仅能提供症状改善。作为大脑中最丰富的神经胶质细胞，星形胶质细胞的数量几乎是神经元的五倍。然而，它们的增殖和转分化潜力使其成为原位神经元替代的理想候选者。直接将星形胶质细胞重编程为神经元提供了一种有前景的再生方法，以恢复受损的神经回路。在此，我们提出一个“汽车启动”模型来概念化这一过程，强调需要抑制非神经元命运途径（松开手刹）、抑制转录抑制因子（松开脚刹）并激活神经元特异性基因表达（踩油门）。此外，克服细胞质中的代谢障碍对于成功的谱系转换至关重要。病毒或非病毒载体递送重编程因子，而小分子作为代谢和表观遗传燃料以提高效率。总之，我们综述了支持直接将星形胶质细胞重编程为神经元作为衰老大脑中一种可行的再生策略的当前证据。我们还强调了概念性的“汽车启动”模型作为剖析谱系转换分子逻辑的有用框架，并强调其在对抗神经退行性疾病方面的有前景的治疗潜力。
