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

• 批准号: 10343664
• 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
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10343664
• 关键词: AD transgenic mice; Address; Affect; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-42; Animal Model; Autophagocytosis; Biological Markers; Brain; Calcium; Cell Proliferation; Cell model; Cell physiology; Cells; Clinical; Clinical Treatment; Clinical Trials; Cognition; Cytosol; Dantrolene; Data; Dementia; Development; Disease; Endoplasmic Reticulum; Fibroblasts; Functional disorder; Glutamates; Glycine Receptors; Goals; Hippocampus (Brain); Homeostasis; Human; Impaired cognition; Impairment; Inflammatory; Intranasal Administration; 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; Plasma; Proteins; Risk Factors; Rodent; Ryanodine Receptor Calcium Release Channel; Ryanodine Receptors; 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; receptor expression; side effect; stem cells; synaptogenesis

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.

抽象的 治疗阿尔茨海默氏病（AD）靶向淀粉样蛋白的临床试验已有 很大程度上失败了。 CA2+失调可能是一种替代机制。在家族广告（FAD）中， 钙稳态被NMDA（NMDAR）和ryanodine（RYR）过度激活所破坏 受体导致胞质钙增加和随后的认知功能障碍和 神经病理学。 APOE4是零星AD的主要危险因素（SAD），也导致Ca2+ 与NMDAR/RYR相关的失调与激活相关。 Dantrolene，Ryr对手， 临床上可用的药物已被证明可以减轻淀粉样病理学，神经变性， FAD动物模型中的突触和记忆丧失。我们的初步研究表明 鼻内丹特罗伦（Dantrolene）给药废除了5xFAD小鼠的记忆力丧失。此外， Dantrolene促进了来自诱导多能干细胞（IPSC）的神经元分化 通过抑制RYR/NMDAR过度，患有APOE4或家族AD（FAD）的患者 激活。我们的长期目标是检查Dantrolene治疗AD的功效。总体 这项研究的目的是研究丹特罗伦的影响和潜在机制 人类和啮齿动物SAD和FAD细胞中的成年神经发生，以及鼻内的作用 AD转基因小鼠的成人神经发生和认知功能的丹特罗烯给药。 我们的中心假设是鼻内丹特罗烯抑制了过多的激活 AD中的Ryrs和NMDAR并促进成人神经发生，改善认知功能 并减少了AD神经病理学。我们将通过以下特定目标检验假设。 具体目的1。确定丹特罗烯对RYR和NMDAR表达的影响 以及AD中的胞质，线粒体和ER Ca2+浓度以及AD生物标志物 使用来自成纤维细胞的诱导多能干细胞（IPSC）的干细胞，可使任何SAD患者患者 （APOE4风险因素）或FAD（PSEN1突变）以及神经元基因细胞（NPC）分离 从E4FAD（APOE4+5XFAD）和5XFAD转基因特异性目标2进行检查。 Dantrolene在RYR和NMDAR活性，神经发生，增殖和细胞上 来自AD细胞的衍生神经元和神经胶质的功能。使用与SA1相同的单元格。 特定目的3。确定丹特洛烯对成人神经发生的影响 AD动物模型中的功能和神经病理学。我们希望Dantrolene会 促进成人神经发生并恢复认知并减少AD小鼠的AD病理 通过减轻Ryrs和/或NMDAR的过度激活模型，尤其是在 鼻内方法。