“通督调神针”通过调节Gamma振荡改善3xTg-AD小鼠认知障碍的分子机制

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with increasing morbidity among aging populations worldwide. Amyloid β peptide (Aβ) deposits and tau tangles have been recognized as two prominent pathological hallmarks for AD. Olfactory dysfunction and spatial perception impairment are common problems/ earliest symptoms in early-stage AD (Mild cognitive impairment). The brains of people with Alzheimer’s show desynchronized electrical activity and loss of oscillatory activity, particularly of gamma-frequency oscillations. We recently reported that a significant increase in DOWN-state duration of slow oscillations due to enhanced inhibition (resulted from reduced GABABR levels and GABA content) in the PFC of AD mouse model. On the other hand, several recent exciting reports have shown that mice carrying genetic mutations that cause Alzheimer’s in humans display reduced gamma oscillations and restoration of normal gamma oscillations via optogenetic stimulation or transgenic overexpression of voltage-gated sodium channels can reduce Aβ deposits and memory deficits. Meanwhile, numerous clinical reports have shown that AD patients exhibit improved cognitive performance after acupuncture. However, whether acupuncture can effectively regulate gamma oscillations, thereby improving cognitive performance; if so, the underlying mechanisms remain to be addressed. Here, we propose to utilize molecular biology, immunohistochemical, electrophysiological and behavioral techniques in 3xTg-AD mice to: 1. assess if “Tong Du Tiao Shen” acupuncture improves olfactory and spatial memory deficits; 2. assess if the “Tong Du Tiao Shen” acupuncture effectively regulates Gamma oscillation; 3: determine the relationship between the effects of acupuncture on Gamma oscillation and olfaction and spatial memory and the underlying molecular and cellular mechanisms. The studies will unravel the underlying mechanisms of acupuncture treatments on AD and should have important implications in the development of new TMC therapy for these devastating diseases.

阿尔茨海默症是一种神经退行性疾病，表征为Aβ沉淀和tau蛋白过度磷酸化引起神经纤维缠结。近来针对Aβ沉淀的临床试验相继失败，揭示可能存在其他主要致病机理。已知AD患者在Aβ沉淀和神经纤维缠结发生之前，嗅觉和空间记忆已发生损伤。申请人前期工作表明，AD小鼠大脑皮层神经网络活动发生异常。新近研究也表明，增强海马伽马振荡可降低Aβ沉淀改善认知障碍。同时，多项临床观察表明，针刺疗法对AD认知障碍的治疗具有一定疗效。然而，针刺疗法如何改善认知障碍的分子机制目前尚不清楚。本课题将采用3xTg-AD转基因小鼠模型，运用分子生化、膜片钳、在体多通道记录和行为学测试等方法，探究针刺“百会”、“大椎”穴位：1.能否改善小鼠嗅觉和空间记忆功能；2.调节伽马振荡神经网络活动；3. 两者的因果关系，并进一步揭示分子细胞机制。本课题的完成，为针灸治疗AD提供临床前现代生物学数据，同时为中国传统医学防治AD提供新思路。

阿尔茨海默症是一种神经退行性疾病，其表征为Aβ沉淀和tau蛋白过度磷酸化引起的神经纤维缠结。但近来一系列针对Aβ沉淀的临床试验相继失败，揭示可能存在其他的主要致病机理。已知AD患者在Aβ沉淀和神经纤维缠结发生之前(轻度认知障碍阶段)，嗅觉和空间记忆已发生损伤。申请人前期工作表明，AD小鼠大脑皮层神经网络活动发生异常。新近研究也表明，增强海马Gamma振荡可降低Aβ沉淀，改善认知障碍。同时，多项临床观察表明，针刺疗法对AD认知障碍的治疗具有一定的疗效。然而，针刺疗法如何缓解和改善认知障碍的分子机制目前尚不清楚。本课题采用3xTg-AD转基因小鼠模型，运用分子生物学、免疫组化、膜片钳、在体多通道记录和行为学测试等方法，发现针刺“百会”、“大椎”穴位：1. 能够改善小鼠嗅觉和空间记忆等行为学功能；2.电针能够改善3xTg-AD小鼠Gamma振荡神经网络活动的异常。本课题的完成，为针灸治疗AD提供临床前现代生物学数据，同时为中国传统医学防治AD提供新思路。