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

摘要 这种多等电点拨款应用的广泛的、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回路的功能障碍 据推测，LEC神经元和投射早期选择性易损性的原因尚不清楚。我们 将检验神经元钙信号失控在LEC-HPC通路中起关键作用的假说 阿尔茨海默病早期的功能障碍。具体地说，在AD的APPKI小鼠模型实验中，我们将研究 如果两个关键蛋白的活性正常化，钙依赖的磷酸酶钙调神经磷酸酶(CaN)或 Prolyl异构酶Pin1早期修复LEC-HPC通讯、功能和稳定性缺陷 广告。Pin1是CaN介导的神经元抑制的关键靶点，直接导致突触和神经元的丢失。在……里面 用APPKI小鼠进行的实验，我们还将确定显性负值Pin1是否会加速 APPKI小鼠LEC-HPC通讯与CAN正常化无关。我们将结合使用 分子、生化、成像、电生理、行为和神经病理学技术 这些具体目标。拟议的研究，如果成功，将提供对早期AD的机械性理解 以及使用CaN抑制剂如FK506或Volosporin来治疗早期AD的理论基础。

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 the LEC-HPC circuit has been implicated, the cause of the early, selective vulnerability of LEC neurons and projections remain unknown. 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 two key proteins, the Ca2+-dependent phosphatase calcineurin (CaN) or the prolyl isomerase, Pin1 rescues defects in LEC–HPC communication, function and stability in early AD. Pin1 is a key target of CaN-mediated inhibition in neurons, directly leading to synaptic and neuronal loss. In experiments with APPKI mice, we will also determine if dominant negative Pin1 accelerates defects in LEC–HPC communication irrespective of CaN normalization in APPKI mice. We will use a combination of molecular, biochemical, imaging, electrophysiological, behavioral and neuropathological techniques to address these specific aims. The proposed studies, if successful, will provide a mechanistic understanding of early AD evolution as well as a rationale for the use of CaN inhibitors such as FK506 or voclosporin to treat early AD.