Institute of Neurological Disease, West China Hospital, Sichuan University, Chengdu, China.
Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia.
Eur J Neurosci. 2022 Oct;56(8):5299-5318. doi: 10.1111/ejn.15810. Epub 2022 Sep 7.
The interaction of neurotrophins with their receptors is involved in the pathogenesis and progression of various neurological diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury and acute and chronic cerebral damage. The p75 neurotrophin receptor (p75NTR) plays a pivotal role in the development of neurological dysfunctions as a result of its high expression, abnormal processing and signalling. Therefore, p75NTR represents as a vital therapeutic target for the treatment of neurodegeneration, neuropsychiatric disorders and cerebrovascular insufficiency. This review summarizes the current research progress on the p75NTR signalling in neurological deficits. We also summarize the present therapeutic approaches by genetically and pharmacologically targeting p75NTR for the attenuation of pathological changes. Based on the evolving knowledge, the role of p75NTR in the regulation of tau hyperphosphorylation, Aβ metabolism, the degeneration of motor neurons and dopaminergic neurons has been discussed. Its position as a biomarker to evaluate the severity of diseases and as a druggable target for drug development has also been elucidated. Several prototype small molecule compounds were introduced to be crucial in neuronal survival and functional recovery via targeting p75NTR. These small molecule compounds represent desirable agents in attenuating neurodegeneration and cell death as they abolish activation-induced neurotoxicity of neurotrophins via modulating p75NTR signalling. More comprehensive and in-depth investigations on p75NTR-based drug development are required to shed light on effective treatment of numerous neurological disorders.
神经营养因子与其受体的相互作用参与了各种神经疾病的发病机制和进展，包括阿尔茨海默病、帕金森病、肌萎缩侧索硬化症、脊髓损伤以及急性和慢性脑损伤。p75 神经营养因子受体（p75NTR）由于其高表达、异常加工和信号转导，在神经功能障碍的发展中起着关键作用。因此，p75NTR 是治疗神经退行性变、神经精神障碍和脑血管功能不全的重要治疗靶点。本文综述了 p75NTR 信号在神经功能缺损中的研究进展。我们还总结了目前通过基因和药理学靶向 p75NTR 来减轻病理变化的治疗方法。基于不断发展的知识，讨论了 p75NTR 在调节 tau 过度磷酸化、Aβ代谢、运动神经元和多巴胺能神经元变性中的作用。还阐明了其作为评估疾病严重程度和作为药物开发的可用药靶标的地位。介绍了几种原型小分子化合物，它们通过靶向 p75NTR 对神经元的存活和功能恢复至关重要。这些小分子化合物通过调节 p75NTR 信号转导，消除神经营养因子激活诱导的神经毒性，从而在减轻神经退行性变和细胞死亡方面具有很大的应用潜力。需要对基于 p75NTR 的药物开发进行更全面和深入的研究，以阐明对多种神经疾病的有效治疗方法。
