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Mechanisms of Dantrolene Neuroprotection in Alzheimer's Disease

丹曲林对阿尔茨海默病的神经保护机制

基本信息

批准号：
10570995
负责人：
HUAFENG WEI
金额：
$ 40.25万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10570995
关键词：
AD transgenic mice Affect Agonist Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer’s disease biomarker Amyloid Amyloid beta-42 Animal Disease Models Animal Model Autophagocytosis Biological Markers Brain Calcium Cell Proliferation Cell Separation Cell membrane Cell model Cell physiology Cells Clinical Clinical Treatment Clinical Trials Cognition Cytosol Dantrolene Data Dementia Development Disease Disease model Endoplasmic Reticulum Fibroblasts Functional disorder Glutamates Glycine Receptors Goals Hippocampus Homeostasis Human Impaired cognition Impairment Inflammatory Intranasal Administration Membrane Memory Loss Messenger RNA Mitochondria Mus Mutation N-Methyl-D-Aspartate Receptors N-Methylaspartate Nerve Degeneration Neurites Neurodegenerative Disorders Neuroglia Neuronal Differentiation Neurons Oral Pathologic Pathology Patients Persons Pharmaceutical Preparations Proliferating Proteins Risk Factors Rodent Ryanodine Ryanodine Receptor Calcium Release Channel Site Skin Synapses Testing Transgenic Animals Transgenic Mice Transgenic Organisms Treatment Efficacy adult neurogenesis amyloid pathology antagonist apolipoprotein E-4 cognitive function cytokine dentate gyrus efficacy evaluation experimental study familial Alzheimer disease improved induced pluripotent stem cell migration mouse model nerve stem cell neurogenesis neuropathology neuroprotection presenilin-1 receptor side effect stem cells synaptogenesis

项目摘要

Abstract Clinical trials for the treatment of Alzheimer's disease (AD) targeting amyloid have largely failed. Ca2+ dysregulation may be an alternative mechanism. In familial AD (FAD), calcium homeostasis is disrupted by over activation of NMDA (NMDAR) and ryanodine (RYR) receptors leading to increased cytosolic calcium and subsequent cognitive dysfunction and neuropathology. APOE4, a major risk factor for sporadic AD (SAD), also causes Ca2+ dysregulation related to NMDAR/RYR over activation. Dantrolene, a RYR antagonist and clinically available drug, has been shown to mitigate amyloid pathology, neurodegeneration, synaptic and memory loss in a FAD animal model. Our preliminary studies suggested that intranasal dantrolene administration abolished memory loss in 5XFAD mice. Furthermore, dantrolene promoted neuronal differentiation in induced pluripotent stem cells (iPSC) from patients with either SAD with APOE4 or familial AD (FAD) by inhibition of RYR/NMDAR over- activation. Our long term goal is to examine the efficacy of dantrolene to treat AD. The overall objective of this study is to investigate the effects and underlying mechanisms of dantrolene on adult neurogenesis in human and rodent SAD and FAD cells, as well as the effects of intranasal dantrolene administration on adult neurogenesis and cognitive function in AD transgenic mice. Our central hypothesis is that intranasal dantrolene inhibits the excessive activation of RYRs and NMDARs in AD and promotes adult neurogenesis, improved cognitive function and reduced AD neuropathology. We will test the hypothesis by the following specific aims. Specific Aim 1. To determine the effects of dantrolene on RYR and NMDAR expression and on cytosolic, mitochondrial, and ER Ca2+ concentrations and AD biomarkers in AD stem cells using induced pluripotent stem cells (iPSC) from fibroblasts patients with either SAD (APOE4 risk factor) or FAD (PSEN1 mutations), as well as neuroprogenitor cells (NPC) isolated from E4FAD (APOE4+5XFAD) and 5XFAD transgenic Specific Aim 2. To examine the effects of dantrolene on RYR and NMDAR activity, neurogenesis, proliferation, and the cellular function of derived neurons and glia from AD cells. using the same cells as in SA1. Specific Aim 3. To determine the effects of dantrolene on adult neurogenesis, cognitive function, and neuropathology in animal models of AD. We expect that dantrolene will promote adult neurogenesis and restore cognition and reduce AD pathology in AD mouse models by alleviating the excessive activation of RYRs and/or NMDARs, especially with the intranasal approach.

摘要针对淀粉样蛋白治疗阿尔茨海默病（AD）的临床试验已经基本上失败了。Ca 2+失调可能是一种替代机制。在家族性AD（FAD）中，钙稳态被NMDA（NMDAR）和兰尼碱（RYR）的过度激活破坏受体，导致细胞溶质钙增加和随后的认知功能障碍，神经病理学APOE 4是散发性AD（SAD）的主要危险因素，也可导致Ca 2 + 与NMDAR/RYR过度激活相关的失调。丹曲林，一种RYR拮抗剂，临床上可获得的药物，已经显示减轻淀粉样蛋白病理，神经变性， FAD动物模型中突触和记忆丧失。我们的初步研究表明，鼻内丹曲林给药消除了5XFAD小鼠的记忆丧失。此外，委员会认为，丹曲林促进来自人的诱导多能干细胞（iPSC）的神经元分化通过抑制RYR/NMDAR过度表达， activation.我们的长期目标是检查丹曲洛林治疗AD的功效。整体本研究的目的是研究丹曲林对大鼠脑缺血再灌注损伤的作用及其机制。人和啮齿动物SAD和FAD细胞中的成体神经发生，以及鼻内给药的影响丹曲林给药对AD转基因小鼠成年神经发生和认知功能的影响。我们的中心假设是，鼻内丹曲林抑制过度激活 RYR和NMDAR在AD中促进成人神经发生，改善认知功能和减少AD神经病理学。我们将通过以下具体目标来检验这一假设。具体目标1.确定丹曲林对RYR和NMDAR表达的影响以及AD患者的细胞溶质、线粒体和ER Ca 2+浓度和AD生物标志物使用来自患有SAD或SAD的成纤维细胞患者的诱导多能干细胞（iPSC）（APOE 4风险因子）或FAD（PSEN 1突变），以及分离的神经祖细胞（NPC 来自E4 FAD（APOE 4 +5XFAD）和5XFAD转基因特异性Aim 2。若要检查效果丹曲林对RYR和NMDAR活性、神经发生、增殖和细胞凋亡的影响从AD细胞衍生的神经元和神经胶质的功能。使用与SA 1中相同的细胞。具体目标3。为了确定丹曲林对成人神经发生、认知功能和神经发育的影响，功能和神经病理学。我们认为丹曲洛林促进AD小鼠成年期神经发生和恢复认知，减轻AD病理通过减轻RYR和/或NMDAR的过度激活，特别是使用鼻内途径。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Oxygen therapy strategies and techniques to treat hypoxia in COVID-19 patients.

氧疗法策略和技术治疗COVID-19患者缺氧的技术。

DOI：
10.26355/eurrev_202010_23248
发表时间：
2020-10
期刊：
European review for medical and pharmacological sciences
影响因子：
3.3
作者：
通讯作者：

Controversies in airway management of COVID-19 patients: updated information and international expert consensus recommendations.

DOI：
10.1016/j.bja.2020.10.029
发表时间：
2021-03
期刊：
British journal of anaesthesia
影响因子：
9.8
作者：
Wei H;Jiang B;Behringer EC;Hofmeyr R;Myatra SN;Wong DT;Sullivan EPO;Hagberg CA;McGuire B;Baker PA;Li J;Pylypenko M;Ma W;Zuo M;Senturk NM;Klein U
通讯作者：
Klein U

Dantrolene repurposed to treat sepsis or septic shock and COVID-19 patients.