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) 的潜在机制仍不清楚，阻碍了阿尔茨海默病的发展新的有效疗法，人们普遍认为钙（Ca2+）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 Ca2+ 释放通道/兰尼碱受体 (RyR2) 泄漏其他人也支持这一假设。研究表明，丹曲林作用于 RyR 通道，可改善认知功能并减少 Aβ 斑块然而，由于 RyR2 功能障碍的机制及其影响，AD 小鼠还需要做更多的工作。 AD 中异常细胞内 Ca2+ 处理和 Aβ 斑块的相关性仍然难以捉摸。证明大脑中的 RyR2 通道渗漏是由 PKA 过度磷酸化、氧化/S-引起的亚硝基化以及通道中稳定亚基 calstabin2 的耗尽，在应激过程中发挥着关键作用。使用具有显着认知功能的 PTSD 慢性束缚应激小鼠模型诱导认知功能障碍功能障碍（Liu et al, Cell 2012）。施用 S107，这是 PI 实验室开发的一种新型 Rycal，可稳定 RyR-calstabin 相互作用并防止细胞内 Ca2+ 泄漏，或通过基因消除 RyR2 PKA 磷酸化位点 Ser2808 (S2808) 在小鼠中（RyR2-S2808A+/+ 敲入），表明病因学中存在 RyR2 渗漏和肾上腺素信号传导我们的新初步数据表明，RyR2 在人类 AD 中存在通道。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-亚硝基化，并耗尽稳定亚基 calstabin2，这是一种生化“特征” 通过基因或药物预防 RyR2 泄漏使 Ca2+ 信号传导正常化，减少 APP+/-/PS1+/- 和 3XTg-AD 中淀粉样斑块的形成 (APPswe/PS1Psen1/TauP301L) 小鼠，改善学习和记忆以及长时程增强 (LTP) 通过基因方法，我们发现具有 RyR2 泄漏的敲入小鼠。通道（RyR2-S2808D+/+ 敲入）具有海马 RyR2 渗漏和过早认知功能障碍。目标是：目标 1) AD 中 RyR 介导的病理性钙失调：识别上游信号。 RyR 介导 AD 中的病理性钙失调：识别下游信号目标 3) 确定关键信号。 AD 发病机制中的钙依赖性机制。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mitochondrial Calcium Overload Plays a Causal Role in Oxidative Stress in the Failing Heart.

线粒体钙超载在心脏衰竭的氧化应激中起着因果作用。

DOI：
发表时间：
2023-09-19
期刊：
影响因子：
5.5
作者：
Dridi, Haikel;Santulli, Gaetano;Bahlouli, Laith;Miotto, Marco C;Weninger, Gunnar;Marks, Andrew R
通讯作者：
Marks, Andrew R