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：
10733805
负责人：
Ilya B Bezprozvanny
金额：
$ 73.08万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10733805
关键词：
Acceleration Address Age Months Alzheimer&apos s Disease Alzheimer&apos s disease model Applications Grants Behavioral Biochemical Calcineurin Calcineurin inhibitor Calcium Calcium Signaling Cell Death Cognitive Communication Data Defect Dementia Dependovirus Detection Development Disease Dominant-Negative Mutation Doxycycline Elderly Electrophysiology (science)Evaluation Evolution FK506 Functional disorder Health Hippocampus Human Image Impaired cognition In Vitro Incidence Label Laboratories Lateral Learning Light Mediating Memory impairment Microscopy Molecular Mus Neurodegenerative Disorders Neurons Outcome Pathogenesis Pathology Patients Peptidylprolyl Isomerase Peripheral Pharmaceutical Preparations Play Proteins Public Health Publishing Research Personnel Resistance Role Schedule Signal Transduction Slice Structure Synapses Talents Techniques Testing Therapeutic Agents Therapeutic Intervention Tissues Transplant Recipients behavioral study calcineurin phosphatase cognitive function conditioned fear dentate gyrus dosage effective therapy entorhinal cortex excitatory neuron experience experimental study in vivo innovation loss of function microscopic imaging mouse model mutant network dysfunction neuron loss neuropathology neuroprotection novel object recognition overexpression promoter prospective public health relevance restoration structural imaging 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 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.

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）。虽然LEC-HPC电路的功能障碍是实施的是，LEC神经元和项目的早期选择性脆弱性的原因仍然未知。我们将检验以下假设：神经元Ca2+信号传导的失调在LEC-HPC电路中起关键作用早期广告功能障碍。具体而言，在使用Appki鼠标AD模型的实验中，我们将研究如果两种关键蛋白的活性归一化，则依赖Ca2+依赖性磷酸酶钙调蛋白（CAN）或 PROLYL异构酶PIN1响应LEC -HPC通信，功能和稳定性的缺陷广告。 PIN1是CAN介导的神经元抑制的关键靶标，直接导致突触和神经元丧失。在使用Appki小鼠进行的实验，我们还将确定显性负PIN1是否会加速缺陷 LEC – HPC通信与Appki小鼠的CAN标准化无关。我们将结合分子，生化，成像，电生理学，行为和神经病理学技术来解决这些具体目标。拟议的研究（如果成功）将提供对早期AD的机械理解进化以及使用CAN抑制剂（例如FK506或VOCLosporin）治疗早期AD的基本原理。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

SpineTool is an open-source software for analysis of morphology of dendritic spines.

DOI：
10.1038/s41598-023-37406-4
发表时间：
2023-06-29
期刊：
SCIENTIFIC REPORTS
影响因子：
4.6
作者：
Ekaterina, Pchitskaya;Peter, Vasiliev;Smirnova, Daria;Vyacheslav, Chukanov;Ilya, Bezprozvanny
通讯作者：
Ilya, Bezprozvanny