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

摘要 这个多PI补助金申请的广泛，长期目标是了解钙（Ca 2+）的作用 作为外侧内嗅皮层（LEC）和 海马体（HPC）在阿尔茨海默病（AD）演变中的作用。虽然LEC-HPC回路功能障碍已被 与AD的早期阶段有关，这是LEC神经元早期选择性脆弱性的原因， LEC-HPC连接的中断仍然未知。在我们的研究中，我们将测试假设， 神经元Ca 2+信号的失调在早期AD的LEC-HPC回路功能障碍中起关键作用。 具体地，在用AD的APPKI小鼠模型的实验中，我们将研究AD的正常化是否会影响AD的正常化。 Ca 2+依赖性磷酸酶钙调神经磷酸酶（CaN）的活性挽救了LEC-HPC中的缺陷 早期AD的通信肽基脯氨酰异构酶Pin 1是神经元中CaN的关键靶点之一。 CaN的升高抑制Pin 1，直接导致突触和神经元损失。在APPKI实验中， 在小鼠中，我们将确定Pin 1活性的恢复是否能挽救LEC-HPC通讯中的缺陷， 早期AD我们将结合分子、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个 使用CaN抑制剂治疗早期AD的机制原理，可能纠正早期功能障碍， LEC-HPC电路和减缓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.