Phospholipase D1 Mediated Early Events Affecting Synaptic Dysfunction in Alzheimer's Disease and Related Dementia

磷脂酶 D1 介导影响阿尔茨海默病和相关痴呆症突触功能障碍的早期事件

• 批准号: 9974025
• 负责人: BALAJI KRISHNAN
• 金额: $ 39.5万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9974025
• 关键词: 3xTg-AD mouse; AD transgenic mice; Address; Affect; Age; Age of Onset; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease related dementia; Amyloid; Attention; Automobile Driving; Autopsy; Behavioral; Biochemical; Brain; C57BL/6 Mouse; Cause of Death; Clinical Trials; Co-Immunoprecipitations; Cognitive deficits; Data; Dementia; Dendritic Spines; Development; Disease; Electrophysiology (science); Etiology; Event; Fluorescence; Fostering; Frontotemporal Dementia; Functional disorder; Future; Goals; Health; Hippocampus (Brain); Human; Impaired cognition; Knowledge; Long-Term Potentiation; Mechanics; Mediating; Memory; Memory impairment; Mission; Molecular; Nerve Degeneration; Neurons; PRKCA gene; Patients; Phospholipase D; Phospholipases A; Protein Isoforms; Proteins; Proteomics; Public Health; Publishing; Quality of life; Reporting; Research; Role; Signal Transduction; Sirolimus; Synapses; Synaptosomes; Tauopathies; Temporal Lobe; Testing; Therapeutic; Therapeutic Intervention; Transgenic Mice; Treatment Efficacy; United States National Institutes of Health; Up-Regulation; Western Blotting; adeno-associated viral vector; brain tissue; cofilin; effective therapy; halopemide; imaging study; improved; inhibitor/antagonist; insight; mouse model; neuropathology; novel; oAβ; overexpression; phospholipase D1; pre-clinical; preclinical study; prevent; recruit; small hairpin RNA; small molecular inhibitor; small molecule; small molecule inhibitor; synaptic function; tau Proteins; vector

PROJECT SUMMARY/ABSTRACT Despite significant research advances in the past two decades, Alzheimer’s disease (AD) remains the sixth leading cause of death that cannot be prevented, cured or even slowed. Attention has shifted towards under- standing early synaptic events in AD and related dementia (ADRD), resulting in memory deficits. However, the mechanism recruited and leading to synapse dysfunction associated memory deficits remains elusive thus im- peding successful therapeutic intervention. Bridging this critical gap in our current knowledge is the goal of this proposal. We present compelling preliminary results that support our hypothesis that inducible phospholipase D (PLD1) overexpression and the resulting aberrant signaling contributes to the progressive detrimental impact on synapses and subsequent cognitive deficits. We will test our central hypothesis by pursuing the following specific aims: (I) testing how elevated synaptic PLD1 levels/signaling contributes to synaptic dysfunction and memory deficits in ADRD; (II) evaluating the functional contribution of elevated PLD1 in preclinical mouse models and studying partners contributing to ADRD-like synaptic dysfunction and memory deficits. The present project is highly significant because the proposed studies will establish elevated PLD1 and the associated signaling part- ners as key players in promoting vulnerability causing progressive synaptic dysfunction and underlying cognitive deficits. The successful completion of the aims will provide insight into the involved molecular mechanisms and therapeutic possibilities using well-tolerated small molecule PLD1 inhibitor in preventing memory deficits asso- ciated with ADRD progression. The proposed project will improve our scientific understanding of how synaptic dysfunction is mediated by elevated PLD1 and interacting signaling partners in contributing to synaptic vulnera- bility.

项目概要/摘要 尽管过去二十年的研究取得了重大进展，但阿尔茨海默病 (AD) 仍然是第六大疾病 无法预防、治愈甚至减缓的主要原因已经转向不足。 AD 和相关痴呆 (ADRD) 中存在早期突触事件，导致记忆缺陷。 招募并导致与记忆缺陷相关的突触功能障碍的机制仍然难以捉摸，因此， 弥合我们当前知识中的这一关键差距是本次研究的目标。 我们提出了令人信服的初步结果，支持我们的假设：诱导型磷脂酶 D。 (PLD1) 过度表达和由此产生的异常信号传导会导致对健康的渐进性不健康影响 我们将通过追求以下具体内容来检验我们的中心假设。 目标：(I) 测试突触 PLD1 水平/信号传导升高如何导致突触功能障碍和记忆 ADRD 缺陷；(II) 评估临床前小鼠模型中 PLD1 升高的功能贡献； 研究导致 ADRD 样突触功能障碍和记忆缺陷的伙伴。 非常重要，因为拟议的研究将建立升高的 PLD1 和相关的信号传导部分- 神经元是促进脆弱性的关键参与者，导致进行性突触功能障碍和潜在的认知功能 目标的成功完成将有助于深入了解所涉及的分子机制和 使用耐受性良好的小分子 PLD1 抑制剂预防记忆缺陷相关的治疗可能性 拟议的项目将提高我们对突触如何进展的科学理解。 功能障碍是由 PLD1 升高和相互作用的信号传导伙伴介导的，从而导致突触损伤 能力。