内侧隔核-海马胆碱能环路损伤在阿尔茨海默病空间记忆障碍中的作用及机制

Cholinergic impairments and spatial memory deficits are chanracteristic pathology and clinical presentation in Alzeimer’s disease (AD). The medial septum (MS) in basal forebrain is enriched with cholinergic neurons and the hippocampus formation is the key for spatial cognitions, in which CA1 is the subset for information output. To date, it is not identified whether there is a monosynaptic connection between MS and CA1; it is also not known whether this circuit is impaired in the AD and how the impairment contributes to the spatial memory deficits in AD. Based on the current knowledges, we speculate that AD-like accumulation of microtubule-asociated protein tau in MS cholinergic neurons may impair the MS-CA1 circuit, and thus causes spatial memory deficits in AD. By employing the cutting edge technologies, including anteriograde and retrograde monosynaptic/neuron type-specific labelings, optogenetic manipulations, electrophysiology, microdialysis, in vivo microelectrode detections, we will study here the age-dependent alterations of MS-CA1 circuit in AD transgenic mice (3XTg and hTau). By cholinergic neuron- or MS-CA1 circuit-specific overexpression of human tau (hTau), we will also explore whether and how tau accumulation in the cholinergic system impairs the MS-CA1 circuit and the correltion with spatial memory deficits. Finally, we will explore whether environment enrichment or optogenetic stimulation of the MS-CA1 cholinegic circuit can rescue the AD memory deficits. This study will provide new insights for AD pathogenesis and new strategies for protection.

胆碱能神经损伤和空间记忆障碍是AD的早期表现，基底前脑内侧隔核（MS）和海马CA1分别是胆碱能神经富集和空间记忆的核心脑区，但MS-CA1环路在空间记忆以及AD中的作用未见报道。基于国际前沿和申请者的前期研究基础，推测MS区胆碱能神经元中tau蛋白异常聚积可直接或通过因果交替机制，损伤MS-CA1胆碱能环路结构和功能，导致空间记忆障碍。本项目拟采用3XTg和人类野生型全长tau转基因小鼠（hTau，模拟散发型AD）以及在MS胆碱能神经元或MS-CA1胆碱能环路特异性过表达hTau小鼠，联合使用正向和逆向单突触追踪、特异性神经元标记、光遗传、电生理、微透析、在体微电极神经递质/活性分子检测等技术，探讨MS-CV1胆碱能单突触环路损伤在AD空间记忆障碍发生发展中的作用和调节机制；通过丰富环境和特异性环路干预，探索保护胆碱能环路和空间记忆功能的策略。该项目将为AD发病机制和有效干预提供新思路。

阿尔茨海默病（简称AD）是最常见的神经退行性变性病。空间记忆障碍和胆碱能神经元损伤是AD患者的早期表现。海马（HP）和基底前脑（MS）是调控空间记忆的核心脑区。申请团队通过环路示踪技术勾勒了MS-HP胆碱能神经环路，确定其调控空间记忆功能；联合组织化学、行为学等检测已明确AD病程中MS-HP胆碱能神经环路明显损伤，并与htau异常聚集密切相关；电生理及行为学检测，发现MS广泛表达htau及MS胆碱能神经元过表达htau抑制MS胆碱能神经元基础突触传递功能，损伤记忆再巩固，导致空间记忆障碍，光遗传学靶向激活该环路能有效逆转AD样空间记忆障碍；申请者针对tau病变研发的靶向磷酸化tau蛋白的化合物能显著改善AD样空间记忆障碍。以上研究工作完成了本项目研究目标，阐明了AD记忆障碍的胆碱能神经环路机制，并为抗AD治疗的脑深部刺激及药物研发提供了新的靶标和策略。