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

项目概要/摘要 尽管在过去的二十年里取得了重大的研究进展，但阿尔茨海默病（AD）仍然是第六大疾病。 导致死亡的主要原因，无法预防，治愈甚至减缓。注意力已经转移到- 在AD和相关痴呆（ADRD）中，长期存在早期突触事件，导致记忆缺陷。但 机制招募和导致突触功能障碍相关的记忆缺陷仍然难以捉摸，因此， 进行成功的治疗干预。弥合我们现有知识中的这一关键差距是本报告的目标。 提议我们目前令人信服的初步结果，支持我们的假设，诱导型磷脂酶D （PLD 1）过表达和由此产生的异常信号传导有助于对细胞的进行性有害影响。 突触和随后的认知缺陷。我们将通过以下具体步骤来检验我们的中心假设： 目的：（I）测试突触PLD 1水平/信号传导升高如何有助于突触功能障碍和记忆 （II）评估临床前小鼠模型中升高的PLD 1的功能贡献， 研究导致ADRD样突触功能障碍和记忆缺陷的伴侣。目前的项目是 非常重要，因为拟议的研究将建立升高的PLD 1和相关的信号部分- 神经元是促进脆弱性的关键因素，导致进行性突触功能障碍和潜在的认知功能障碍。 赤字这些目标的成功完成将为深入了解所涉及的分子机制提供帮助， 使用耐受性良好的小分子PLD 1抑制剂预防记忆缺陷的治疗可能性 与ADRD进展有关。该项目的提出将提高我们对突触是如何 功能障碍是由升高的PLD 1和相互作用的信号伴侣介导的， 能力

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.