Early Neuronal Signaling Deficits in AD for Novel Therapeutic Development

描述(由申请人提供)： 阿尔茨海默病(AD)是一种毁灭性的神经退行性疾病，以β淀粉样蛋白、tau病理和不可逆转的认知丧失为特征。阿尔茨海默病的病理过程目前尚无明确的认识，也没有有效的治疗方法。最近的研究表明，在AD患者淀粉样蛋白沉积、tau病理、神经元丢失和认知损害之前，IP3R和ryanodine(RyR)钙通道释放的内质网(ER)钙增加。针对这些早期的致病过程可能被证明是AD的一种成功的治疗策略。锂稳定了IP3R过度的钙释放和通过GSK3b上调的tau的过度磷酸化。Dantrolene是一种新型的RyR通道稳定剂，它可以增加RyR的钙释放，并稳定受损的突触可塑性。本研究的目的是探讨IP3R和GSk3b以及RyR介导的钙升高在突触功能障碍和AD病理过程中的作用，以及锂和丹曲林衍生物是否能稳定ER钙通道，阻断突触功能障碍和AD病理。目的：研究锂在AD发病早期的神经保护作用。我们将用锂治疗AD小鼠模型(3xTg-AD)和对照组4周，然后检测AD组织病理级联反应的生化变化，海马区突触完整性，并检测海马区突触可塑性和CA1区海马神经元钙信号的恢复。目的：研究丹曲林衍生物是否能阻断受损的突触功能和完整性。我们将用这些衍生物治疗3xTg-AD和对照组小鼠4周，然后检测突触的可塑性和CA1海马神经元钙信号的完整性和恢复。该项目可能为开发有效治疗阿尔茨海默病的退伍军人开辟一条道路。

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.