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（HPC）在阿尔茨海默病（AD）中的作用。虽然LEC-HPC电路的功能障碍已经被 然而，LEC神经元和投射的早期选择性脆弱性的原因仍然未知。我们 将检验神经元Ca 2+信号失调在LEC-HPC回路中起关键作用的假设 早期AD的功能障碍。具体而言，在AD的APPKI小鼠模型的实验中，我们将研究 如果两个关键蛋白质的活性正常化，即Ca 2+依赖性磷酸酶钙调神经磷酸酶（CaN）或 脯氨酰异构酶Pin 1挽救了早期LEC-HPC通信、功能和稳定性中缺陷 AD. Pin 1是神经元中CaN介导的抑制的关键靶点，直接导致突触和神经元损失。在 我们还将确定显性负性Pin 1是否会加速APPKI小鼠的缺陷， 在APPKI小鼠中，LEC-HPC通信与CaN正常化无关。我们将结合使用 分子、生物化学、成像、电生理、行为和神经病理学技术， 这些具体目标。这些研究如果成功，将为早期AD提供一个机制性的理解。 这是一个新的进展以及使用CaN抑制剂如FK 506或voclosporin治疗早期AD的基本原理。

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.