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Calcium and the Pathophysiology of Neurodegenerative Disorders

钙与神经退行性疾病的病理生理学

基本信息

批准号：
10052965
负责人：
ANDREW Robert MARKS
金额：
$ 231.02万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10052965
关键词：
3xTg-AD mouse APP-PS1 ATP phosphohydrolase Ablation Address Adrenergic Agents Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease therapeutic Amyloid Behavioral Binding Biochemical Biological Assay Biological Markers Brain Calcium Calpain Cell membrane Cells Chronic Clinical Trials Cognition Disorders Cognitive Consensus Cyclic AMP-Dependent Protein Kinases Dantrolene Data Development Dissociation Drug Targeting Drug usage Endoplasmic Reticulum Enzymes Estrogen receptor positive Etiology FKBP1B gene Functional disorder Genetic Glutamate Receptor Goals Hippocampus (Brain)Histopathology Homeostasis Human Human Genetics Hydroxyl Radical ITPR1 gene Impaired cognition Inositol Isoxazoles Knock-in Knock-in Mouse Laboratories Learning Link Long-Term Depression Long-Term Potentiation Malignant hyperpyrexia due to anesthesia Mediating Mediator of activation protein Memory Memory Loss Molecular Probes Mus N-Methylaspartate Neurodegenerative Disorders Neurons Oral Oxidative Stress Oxides Parvalbumins Pathogenesis Pathologic Pathway interactions Performance Pharmacology Phosphorylation Phosphorylation Site Play Post-Translational Protein Processing Post-Traumatic Stress Disorders Propionates Protein Isoforms Reporting Rest Role Ryanodine Receptor Calcium Release Channel Ryanodine Receptors Senile Plaques Signal Transduction Sodium Source Stress Structure Synaptic Transmission Synaptic plasticity Testing Therapeutic Therapeutic Effect Work abeta deposition adrenergic stress aspartate receptor calbindin calmodulin-dependent protein kinase II cell type cognitive function effective therapy familial Alzheimer disease genetic approach improved mouse model neuropathology new therapeutic target novel novel drug class novel therapeutic intervention oxidation premature preservation prevent receptor restraint stress small molecule synaptic function voltage

项目摘要

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.

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 AD患者细胞内钙离子处理异常和A-β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)在小鼠中(RyR2-S2808A+/+敲入)，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” 说明细胞内钙离子渗漏是病理性的。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中淀粉样斑块的形成 (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+/+敲入)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