Zheng Kai, Huang He-Zhou, Liu Dan, Brazhe Nadezda, Chen Jiajie, Zhu Ling-Qiang
Department of Geriatrics Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China.
Department of Pathophysiology School of Basic Medicine Tongji Medical College Huazhong University of Science and Technology Wuhan China.
MedComm (2020). 2025 Sep 6;6(9):e70368. doi: 10.1002/mco2.70368. eCollection 2025 Sep.
Alzheimer's disease (AD) is one of the leading causes of dementia in the elderly, and no effective treatment is currently available. Cathepsin B (CTSB) is involved in key pathological processes of AD, but the underlying mechanisms and its relevance to AD diagnosis and treatment remain unclear. In the present study, we found that CTSB expression was abnormally elevated in the hippocampus of 3×Tg mice and was regulated by miR-96-5p. Abnormalities in the miR-96-5p/CTSB signaling pathway were detected in the serum of both mild cognitive impairment and AD patients, and the combination of serum miR-96-5p and CTSB demonstrated strong diagnostic efficacy for cognitive impairment (AUC = 0.7536). Abnormalities in the miR-96-5p/CTSB signaling pathway in AD may be associated with Aβ pathology, and neuronal CTSB can be released extracellularly to reactivate adjacent astrocytes. Ultimately, the reconstitution of the miR-96-5p/CTSB signaling pathway effectively rescued astrocyte reactivity and memory impairment in AD. Our findings suggest that the neuron-derived inflammatory mediator CTSB reactivates adjacent astrocytes and mediates memory impairment in early AD. The combination of serum miR-96-5p and CTSB represents potential serum biomarkers for cognitive impairment, and targeting the neuronal miR-96-5p/CTSB pathway may serve as a promising therapeutic strategy for AD.
阿尔茨海默病（AD）是老年人痴呆的主要病因之一，目前尚无有效的治疗方法。组织蛋白酶B（CTSB）参与AD的关键病理过程，但其潜在机制及其与AD诊断和治疗的相关性仍不清楚。在本研究中，我们发现CTSB在3×Tg小鼠海马中的表达异常升高，并受miR-96-5p调控。在轻度认知障碍和AD患者的血清中均检测到miR-96-5p/CTSB信号通路异常，血清miR-96-5p和CTSB的联合检测对认知障碍具有较强的诊断效能（AUC = 0.7536）。AD中miR-96-5p/CTSB信号通路异常可能与Aβ病理相关，神经元CTSB可释放到细胞外以重新激活相邻的星形胶质细胞。最终，miR-96-5p/CTSB信号通路的重建有效挽救了AD中的星形胶质细胞反应性和记忆障碍。我们的研究结果表明，神经元衍生的炎症介质CTSB可重新激活相邻的星形胶质细胞并介导早期AD中的记忆障碍。血清miR-96-5p和CTSB的联合检测代表了认知障碍的潜在血清生物标志物，靶向神经元miR-96-5p/CTSB通路可能是一种有前景的AD治疗策略。
