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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.

摘要

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.