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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：
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.

摘要

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