Calcium and the Pathophysiology of Neurodegenerative Disorders

然而，阿尔茨海默病(AD)的发病机制(S)仍然不清楚，阻碍了 新的有效治疗方法，普遍认为钙(Ca~(2+))起作用。我们的假设是 肾上腺素能和氧化应激导致细胞内钙释放通道/兰尼定受体(RyR2)泄漏 导致AD神经病理和认知功能障碍的神经元。为了支持这一假设，其他人已经 研究表明，作用于RyR通道的丹曲林可以改善认知功能，减少β斑块。 广告小鼠。然而，还需要做更多的工作，因为导致RyR2功能障碍的机制和他们的 阿尔茨海默病患者细胞内钙处理异常和Aβ斑块的相关性仍不明确。我们有 证明脑组织中RyR2通道泄漏，由PKA过度磷酸化、氧化/S- 亚硝酸化和从通道中耗尽稳定的亚基calstain2，在应激- 慢性束缚应激性创伤后应激小鼠模型的认知功能障碍 功能障碍(Liu et al，Cell 2012)。应激引起的认知功能障碍可以通过以下两种方式得到挽救 PIS实验室开发的稳定RyR-calstain相互作用的新型Rycal，S107的管理 并防止细胞内钙泄漏，或通过基因消融Ser2808上的RyR2 PKA磷酸化位点 (S2808)在小鼠(RyR2-S2808A/Knoke-in)中，涉及RyR2泄漏和肾上腺素能信号在病因中的作用 阿尔茨海默病相关认知功能障碍。我们新的初步数据显示，人类AD中的RyR2通道 在患者大脑和三种家族性阿尔茨海默病(FAD)小鼠模型中，PKA过度磷酸化， 氧化/S亚硝化，并耗尽稳定的亚基钙调蛋白2，这是一个生化“标志” 说明细胞内钙离子有病理性渗漏。从基因或药物上防止RyR2泄漏 正常化钙信号，减少APP/-/PS1/-和3xTg-AD的淀粉样斑块形成 (APPswe/PS1Psen1/TauP301L)小鼠，并改善学习和记忆以及长时程增强(LTP) 和长期抑郁(LTD)。使用遗传方法，我们发现带有泄漏RyR2基因的敲入小鼠 通道(RyR2-S2808D/Knoking-in)存在海马区RyR2泄漏和过早的认知功能障碍。 目的：1)RyR介导的AD病理性钙失衡：识别上游信号。目标2) RyR介导的AD病理性钙失衡：识别下游信号。目标3)确定关键 钙依赖在阿尔茨海默病发病机制中的作用

While, the mechanism(s) underlying Alzheimer’s Disease (AD) remain obscure, hindering the development of novel effective therapy, there is general consensus that calcium (Ca2+) plays a role. Our hypothesis is that adrenergic and oxidative stress cause a leak in intracellular Ca2+ release channels/ryanodine receptors (RyR2) in neurons resulting in AD neuropathology and cognitive dysfunction. In support of this hypothesis others have shown that dantrolene, which acts on RyR channels, improves cognitive function and reduces Aβ plaques in AD mice. However, more work is needed because the mechanisms causing RyR2 dysfunction and their correlation with abnormal intracellular Ca2+ handling and Aβ plaques in AD remain elusive. We have demonstrated that leaky RyR2 channels in the brain, caused by PKA hyperphosphorylation, oxidation/S- nitrosylation, and depletion of the stabilizing subunit calstabin2 from the channel, play a key role in stress- induced cognitive dysfunction using a chronic restraint stress murine model of PTSD with significant cognitive dysfunction (Liu et al, Cell 2012). The stress-induced cognitive dysfunction was rescued either by administering S107, a novel Rycal developed in the PIs laboratory that stabilizes RyR-calstabin interactions and prevents intracellular Ca2+ leak, or by genetic ablation of the RyR2 PKA phosphorylation site at Ser2808 (S2808) in mice (RyR2-S2808A+/+ knock-in), implicating leaky RyR2 and adrenergic signaling in the etiology of AD associated cognitive dysfunction. Our new preliminary data show that RyR2 channels in the human AD patient brains and in three murine models of familial Alzheimer’s Disease (FAD), are PKA hyperphosphorylated, oxidized/S-nitrosylated, and depleted of the stabilizing subunit calstabin2, a biochemical “signature” that denotes a pathological intracellular Ca2+ leak. Preventing RyR2 leak BOTH genetically or pharmacologically normalizes Ca2+ signaling, reduces amyloid plaque formation in APP+/-/PS1+/- and in 3XTg-AD (APPswe/PS1Psen1/TauP301L) mice, and improves learning and memory as well as long-term potentiation (LTP) and long-term depression (LTD). Using a genetic approach we show that knock-in mice with leaky RyR2 channels (RyR2-S2808D+/+ knock-in) have leaky hippocampal RyR2 and premature cognitive dysfunction. The aims are: Aim 1) RyR-mediated pathological calcium dysregulation in AD: identify upstream signals. Aim 2) RyR mediated pathological calcium dysregulation in AD: identify downstream signals. Aim 3) Determine key calcium dependent mechanisms in AD pathogenesis.