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

阿尔茨海默病中的钙失调和内嗅皮层神经元的脆弱性

基本信息

批准号：
10459711
负责人：
Ilya B Bezprozvanny
金额：
$ 69.82万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10459711
关键词：
Address Age-Months Alzheimer&apos s Disease Alzheimer&apos s disease model Applications Grants Behavioral Biochemical CRISPR interference Calcineurin Calcineurin inhibitor Calcium Communication Consensus Cyclosporine Data Defect Dementia Detection Development Disease Elderly Electrophysiology (science)Evaluation Evolution FDA approved FK506 Functional disorder Health Hippocampus (Brain)Human Image Immunosuppression Impairment Incidence Induced Mutation Label Laboratories Lateral Lead Light Memory impairment Microscopy Molecular Mus Neurodegenerative Disorders Neurons Pathogenesis Pathology Patients Peptidylprolyl Isomerase Peripheral Pharmaceutical Preparations Play Proteins Public Health Publishing Research Personnel Role Signal Transduction Slice Structure Synapses Talents Techniques Testing Therapeutic Agents Therapeutic Intervention Tissues Transplant Recipients behavioral study calcineurin phosphatase conditioned fear effective therapy entorhinal cortex excitatory neuron experience experimental study innovation microscopic imaging mouse model mutant network dysfunction neuron loss novel object recognition overexpression presenilin prospective public health relevance restoration therapeutically effective transplantation therapy vector

项目摘要

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.

抽象的该多PI赠款应用的广泛长期目标是了解钙的作用（CA2+）失调作为机械驱动器的机械驱动力在不断发展的阿尔茨海默氏病（AD）中的海马（HPC）。 LEC-HPC电路的功能障碍已在AD的早期阶段实施，是LEC神经元和 LEC-HPC连接的破坏仍然未知。在我们的研究中，我们将检验以下假设神经元CA2+信号传导的失调在早期AD中的LEC-HPC电路功能障碍中起关键作用。具体而言，在使用Appki小鼠AD模型的实验中，我们将研究是否归一化 Ca2+依赖性磷酸酶钙调蛋白（CA）的活性反应LEC – HPC中的缺陷早期广告中的沟通。肽基 - 培养基异构酶PIN1是神经元中CAN的关键靶标之一。升高可以抑制PIN1，直接导致突触和神经元丧失。在Appki实验中小鼠，我们将确定PIN1活动的恢复是否挽救了LEC – HPC通信中的缺陷早期广告。我们将结合分子，生化，成像，电生理，行为和神经病理技术解决这些特定目标。如果成功，我们的研究将提供使用CAN抑制剂来治疗早期AD的机械原理，可能会纠正早期功能障碍 LEC-HPC电路和AD开发放缓。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A Gating Mutation in Ryanodine Receptor Type 2 Rescues Phenotypes of Alzheimer's Disease Mouse Models by Upregulating Neuronal Autophagy.

2 型 Ryanodine 受体的门控突变通过上调神经元自噬来拯救阿尔茨海默病小鼠模型的表型。

DOI：
10.1523/jneurosci.1820-22.2022
发表时间：
2023
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Zhang,Hua;Knight,Caitlynn;Chen,SRWayne;Bezprozvanny,Ilya
通讯作者：
Bezprozvanny,Ilya

Conformational Models of APP Processing by Gamma Secretase Based on Analysis of Pathogenic Mutations.