阿尔茨海默病早期EW神经元内DAPK1激活的作用与机制研究

Attention, the fundamental component of cognitive function, has been reported to significantly deficit anteceding cognitive impairment as in Alzheimer’s disease (AD). Therefore, improving attentional impairment may delay the emergence of cognitive impairment. Our former studies on AD have remarked that EW neurons substantially contributes for attention are significantly damaged in the early stage of the disease. And we also found DAPK1, can induce neuronal damage through Tau protein phosphorylation as observed in a cerebral ischemia model, was activated in EW neurons. Therefore, we hypothesis that in the early stage of AD, activated DAPK1 in EW neurons induces over-phosphorylation of Tau protein which subsequently result in neuronal damage and attention aberration. This project aims to further investigate the functional role and mechanism of activated DAPK1 in EW neurons at the molecular, cellular and animal model level to contribute to the diagnosis and treatment of AD earlier.

作为认知功能基本要素的注意力，在阿尔茨海默病（Alzheimer's disease，AD）的早期便出现了损伤，且明显早于认知障碍的出现。因此，改善注意力损伤可能可以延缓认知障碍的出现。我们发现，在只表现注意力损伤的AD早期，参与并调控注意力的EW神经元损伤明显（树突棘数量减少），神经元内死亡相关蛋白激酶-1（Death associated protein kinase-1， DAPK1）活性升高。而在脑缺血模型中，激活的DAPK1可通过磷酸化Tau蛋白造成树突棘损伤。所以，我们提出假说：在AD早期，EW神经元内活性上升的DAPK1过度磷酸化Tau蛋白，引起EW神经元损伤，导致活性下降，从而损伤注意力。本项目将从分子、细胞和整体动物水平研究EW神经元内DAPK1激活在AD早期注意力损伤中的作用及机制，为探索AD研究与诊治靶点提供实验依据。

阿尔茨海默病（Alzheimer's disease，AD）又名老年痴呆，是一种进行性发展的神经系统退行疾病。AD 患者一般表现为学习能力下降，记忆缺失，认知障碍，以及语言能力退化，严重影响自理及社交能力。临床上虽无AD的特效治疗手段，但更早的干预能够有效地延缓病程发展，“早发现，早诊断，早治疗，早获益”是AD的诊疗策略。但是，AD起病隐匿，早期缺乏行之有效的检测指标。本项目中，我们对不同月龄的AD模型小鼠进行注意力检测，发现注意力可作为AD早期的行为检测指标，因为注意力损伤的出现远早于认其他经典的知障碍损伤。AD模型小鼠中脑的EW神经元退变与注意力损伤同步出现，并且激活退变的EW神经元可有效改善注意力损伤。此外，我们还发现焦虑样行为及冲动行为也可作为AD的早期行为诊断指标，并且使用AD模型小鼠，揭示了这两种行为产生的相关神经环路。