星型胶质细胞介导的BLP-vCA1神经环路损伤在阿尔茨海默病抑郁和空间记忆障碍中的作用及干预机制研究

Depression and memory deficit are early clinical manifestations of Alzheimer’s disease (AD), and the former has been shown to accelerate memory deficit and the progression of AD. However, the mechanisms remain unclear. In recent study, we found that AD transgenic mice accompanied by depression-like despair behavior exhibited more severe spatial working memory deficits as well as deposit of Aβ-amyloid (Aβ) in posterior part of basolateral amygdala (BLP). We identified an excitatory input from BLP to ventral hippocampal CA1 (vCA1). Activation of BLP-vCA1 input can rescue despair emotion impaired-spatial learning and memory. Inhibition of the inputs can induce significant encoding deficit during spatial working memory. In addition, functional inhibition of astrocyte-specific GABA transporter GAT3/4 not only ameliorated despair emotion but also spatial working memory impairment of AD transgenic mice. These data suggested the detrimental effects of depression on working memory and a vital role of BLP-vCA1 input and GAT3/4 in the pathogenesis of AD. This study is aimed to investigate and elucidate the effects of depression-aggravated spatial working memory deficit and the underlying mechanisms, including the relationship among Aβ, BLP-vCA1 input impairment, AD-like depression and spatial working memory deficit; whether and how Aβ impairs BLP-vCA1 input via GAT3/4, therefore leading to a consequence of AD-like depression-aggravated spatial working memory deficit. Furthermore, whether activation of BLP-vCA1 input and/or inhibition of GABA transporter can rescue AD-like depression and/or its aggravated working memory deficit will be dissected. The accomplishment of this project will be expected to contribute to the discovery of new idea and novel molecular targets for efficient prevention and treatment of AD.

抑郁和记忆障碍是阿尔茨海默病（AD）早期表现，前者可加速、加重记忆损伤，但机制不明。申请者发现：伴抑郁绝望情绪的AD转基因小鼠工作记忆损伤严重且与杏仁核基底外侧核后部（BLP）β-淀粉样肽（Aβ）沉积相关；激活BLP至腹侧海马CA1（vCA1）环路能逆转绝望情绪所致记忆障碍，抑制该环路降低工作记忆的编辑能力；抑制BLP内星型胶质细胞GABA转运体(GAT3/4)具有改善抑郁和工作记忆障碍的双重效应，提示：抑郁对工作记忆的损伤及BLP-vCA1环路、GAT3/4在AD发病和防治中起重要作用。本项目将探讨AD样抑郁产生及其加重工作记忆损伤的机制，包括Aβ与抑郁、BLP-vCA1环路损伤、工作记忆障碍间的关系；Aβ是否通过GAT3/4损伤BLP-vCA1环路，并在AD样抑郁加重工作记忆障碍中发挥关键作用；增强该环路或抑制GAT3/4能否改善抑郁和或记忆损伤。该项目将为AD防治提供新思路和新靶标。