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

项目摘要/摘要 尽管在过去20年中取得了重大的研究进展，但阿尔茨海默病(AD)仍位居第六 无法预防、治愈甚至减缓的主要死因。注意力已经转移到了低于- 阿尔茨海默病和相关痴呆(ADRD)的早期突触事件，导致记忆障碍。然而， 被招募并导致突触功能障碍的机制与记忆障碍相关，因此仍不清楚。 成功地进行了治疗干预。弥合我们当前知识中的这一关键差距是这一目标 求婚。我们提出了令人信服的初步结果，支持我们的假设，即可诱导的磷脂酶D (PLD1)的过度表达和由此产生的异常信号导致了对 突触和随后的认知缺陷。我们将通过追求以下具体内容来测试我们的中心假设 目的：(I)测试突触PLD1水平/信号升高如何有助于突触功能障碍和记忆 ADRD的缺陷；(Ii)评估PLD1升高在临床前小鼠模型和 研究导致类似ADRD的突触功能障碍和记忆障碍的伴侣。目前的项目是 非常重要，因为拟议的研究将建立升高的PLD1和相关的信号部分- NERs在促进易损性导致进行性突触功能障碍和潜在认知方面发挥关键作用 赤字。AIMS的成功完成将为深入了解相关的分子机制和 使用耐受性良好的小分子PLD1抑制剂预防记忆障碍的治疗可能性 与ADRD进展有关。拟议的项目将提高我们对突触如何 功能障碍是由PLD1升高和相互作用的信号伙伴参与促成突触缺陷- 保佑。

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.