Early Neuronal Signaling Deficits in AD for Novel Therapeutic Development

描述（由申请人提供）： 阿尔茨海默病（Alzheimer's disease，AD）是一种以β淀粉样蛋白、tau蛋白和不可逆的认知功能丧失为特征的神经退行性疾病。目前对AD的病理过程和有效治疗方法还没有明确的认识。最近的研究表明，增加的内质网（ER）的钙释放从IP 3R和ryanodine（RyR）钙通道之前淀粉样蛋白沉积，tau病理，神经元损失，和认知障碍的AD。靶向这些早期致病过程可能被证明是AD的成功治疗策略。锂可稳定IP 3R的过度钙释放和通过GSK 3b上调的tau过度磷酸化。RyR增加钙释放和受损的突触可塑性是稳定的丹曲林，一种新的RyR通道稳定剂。本项目的目的是探索IP 3R和GSk 3b以及RyR介导的钙离子增加在突触功能障碍和AD病理过程中的作用，以及锂和丹曲林衍生物是否可以稳定ER钙通道并阻断突触功能障碍和AD病理。目的1：证实锂在AD发病早期具有神经保护作用。我们将用锂处理AD小鼠模型（3xTg-AD）和对照4周，然后检查指示AD的组织病理学级联的生化变化、海马突触完整性，并且还检查海马突触可塑性和CA 1海马神经元中钙信号传导的恢复。目的2：检测丹曲林衍生物是否阻断受损的突触功能和完整性。我们将用衍生物处理3xTg-AD和对照小鼠4周，然后检查CA 1海马神经元中突触可塑性和钙信号传导的完整性和恢复。该项目可以为开发有效治疗AD退伍军人的方法开辟一条道路。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a devastating neurodegenerative disease, characterized by beta amyloid, tau pathology and irreversible cognitive loss. Neither clear understanding of the pathological process nor the effective treatment of AD is available at present. Recent research indicates that increased endoplasmic reticulum (ER) calcium release from IP3R and ryanodine (RyR) calcium channels precedes amyloid deposition, tau pathology, neuronal loss, and cognitive impairments in AD. Targeting these early pathogenic processes may prove to be a successful therapeutic strategy of AD. Excessive calcium release from IP3R and hyperphosphorylation of tau via GSK3b upregulation is stabilized by lithium. RyR increases calcium release and impaired synaptic plasticity is stabilized by dantrolene, a novel RyR-channel stabilizer. The purpose of this project is to explore the role of IP3R and GSk3b and that of RyR-mediated calcium increase in synaptic dysfunction and AD pathological process and whether lithium and dantrolene derivatives can stabilize ER calcium channels and block synaptic dysfunction and AD pathology by pursuing two objectives below. Objective 1: Demonstrate that lithium serves as a neuroprotective agent during early stage of AD pathogenesis. We will treat AD mouse models (3xTg-AD) and controls with lithium for 4 weeks, and then examine biochemical changes indicative of histopathological cascades of AD, hippocampal synaptic integrity and also examine hippocampal synaptic plasticity and restoration of calcium signaling in CA1 hippocampal neurons. Objective 2: Examine whether dantrolene derivatives block impaired synaptic function and integrity. We will treat 3xTg-AD and control mice with the derivatives for 4 weeks, and then examine synaptic plasticity and integrity and restoration of calcium signaling in CA1 hippocampal neurons. This project could open a pathway to the development of an effective treatment of veterans with AD.