Calcium and the Pathophysiology of Neurodegenerative Disorders

然而，阿尔茨海默病（AD）的潜在机制仍然不清楚，阻碍了阿尔茨海默病（AD）的发展。 新的有效的治疗，有一个普遍的共识，钙（Ca 2+）发挥作用。我们的假设是 肾上腺素能和氧化应激导致细胞内Ca 2+释放通道/兰尼碱受体（RyR 2）泄漏 导致AD神经病理学和认知功能障碍。为了支持这一假设， 表明作用于RyR通道的丹曲林可改善认知功能并减少Aβ斑块， AD小鼠。然而，还需要更多的工作，因为导致RyR 2功能障碍的机制和它们的作用机制还不清楚。 与AD中异常细胞内Ca 2+处理和Aβ斑块的相关性仍然不清楚。我们有 证明了脑中由PKA过度磷酸化、氧化/S- 亚硝酰化和通道中稳定亚基钙蛋白2的耗尽在应激中起关键作用。 使用具有显着认知功能的慢性束缚应激创伤后应激障碍小鼠模型诱导认知功能障碍 功能障碍（Liu等，Cell 2012）。压力引起的认知功能障碍可以通过 施用S107，一种在PI实验室开发的新型Rycal，其稳定RyR-钙稳定蛋白相互作用 并防止细胞内Ca 2+泄漏，或通过基因切除RyR 2 PKA磷酸化位点Ser 2808 （S2808）在小鼠（RyR 2-S2808 A +/+敲入）中的表达，表明RyR 2和肾上腺素能信号传导渗漏在病因学中 AD相关的认知功能障碍我们新的初步数据显示，人类AD中的RyR 2通道 患者脑和家族性阿尔茨海默病（FAD）的三种鼠模型中，PKA被过度磷酸化， 氧化/S-亚硝基化，并耗尽稳定亚基钙稳定蛋白2，这是一种生化“特征”， 表示病理性细胞内Ca 2+渗漏。防止RyR 2泄漏遗传或遗传 使Ca 2+信号正常化，减少APP+/-/PS1+/-和3XTg-AD中的淀粉样斑块形成 （APPswe/PS1 Psen 1/TauP 301 L）小鼠，并改善学习和记忆以及长时程增强（LTP） 长期抑郁症（LTD）使用遗传学方法，我们表明敲入RyR 2泄漏的小鼠， 通道（RyR 2-S2808 D +/+敲入）具有海马RyR 2渗漏和过早认知功能障碍。 目的1）AD中RyR介导的病理性钙调节异常：识别上游信号。目标2） RyR介导的AD病理性钙失调：识别下游信号目标3）确定关键 AD发病机制中的钙依赖机制。

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.