Calcium dysregulation and vulnerability of entorhinal cortex neurons in Alzheimer's disease

摘要 这项多PI拨款应用的广泛、长期的目标是了解钙(钙)的作用。 调节失调是外侧内嗅皮层和下丘脑之间突触丢失的机制驱动因素 进行性阿尔茨海默病(AD)中的海马区(HPC)。而LEC-HPC回路功能障碍 与AD的早期阶段有关，这种早期的、选择性的LEC神经元和 LEC-HPC连接的中断情况仍不得而知。在我们的研究中，我们将检验这一假设 神经元钙信号的失调在早期AD的LEC-HPC通路功能障碍中起着关键作用。 具体地说，在AD的APPKI小鼠模型的实验中，我们将研究AD的正常化 钙依赖磷酸酶钙调神经磷酸酶(CaN)活性修复LEC-HPC缺陷 公元早期的交流。肽基-脯氨酰异构酶Pin1是神经元内CaN的关键靶点之一。 In的升高可以抑制Pin1，直接导致突触和神经元的丢失。在使用APPKI的实验中 小鼠，我们将确定Pin1活性的恢复是否可以挽救LEC-HPC通信的缺陷 公元早期。我们将使用分子、生化、成像、电生理、行为和 神经病理学技术来解决这些特定的目标。如果成功，我们的研究将提供一种 使用CaN抑制剂治疗早期AD的机制基础，潜在地纠正早期AD的功能障碍 LEC-HPC电路和减慢AD开发。

ABSTRACT The broad, long-term objective of this multi-PI grant application is to understand the role of calcium (Ca2+) dysregulation as the mechanistic driver for synaptic loss between the lateral entorhinal cortex (LEC) and hippocampus (HPC) in evolving Alzheimer’s disease (AD). While dysfunction of LEC-HPC circuit has been implicated in the early stages of AD, the cause of this early, selective vulnerability of LEC neurons and disruption of LEC-HPC connections remain unknown. In our studies we will test the hypothesis that dysregulation of neuronal Ca2+ signaling plays a key role in LEC-HPC circuit dysfunction in early AD. Specifically, in experiments with the APPKI mouse model of AD, we will investigate if normalization of the activity of the Ca2+-dependent phosphatase calcineurin (CaN) rescues defects in LEC–HPC communication in early AD. The peptidyl-prolyl isomerase Pin1 is one of the key targets of CaN in neurons. Elevations in CaN inhibit Pin1, directly leading to synaptic and neuronal loss. In experiments with APPKI mice, we will determine if restoration of Pin1 activity rescues defects in LEC–HPC communication in early AD. We will use a combination of molecular, biochemical, imaging, electrophysiological, behavioral and neuropathological techniques to address these specific aims. If successful, our studies will provide a mechanistic rationale for the use of CaN inhibitors to treat early AD, potentially correcting early dysfunction of the LEC-HPC circuit and slowing AD development.