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The contribution of Ly6h to Alzheimers Disease

Ly6h 对阿尔茨海默病的贡献

基本信息

批准号：
10591330
负责人：
William J Joiner
金额：
$ 23.7万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10591330
关键词：
Age Alzheimer disease detection Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer’s disease biomarker Amyloid beta-Protein Animal Model Animals Behavior Behavioral Biological Assay Blood Cell Line Cerebrospinal Fluid Chronic Clinical Data Cognition Complement Data Disease Disease Progression Disinhibition Down-Regulation Early Diagnosis Effectiveness Elements Enzyme-Linked Immunosorbent Assay Etiology Exhibits FDA approved Goals Hippocampus Impaired cognition In Vitro Individual Lentivirus Link Measurement Measures Memory Memory Loss Methods Molecular Molecular Conformation Mus Nerve Degeneration Neurobehavioral Manifestations Neurons Nicotinic Receptors Outcome Pathogenesis Pathogenicity Pathway interactions Peptides Performance Permeability Pharmaceutical Preparations Physiological Predisposition Prevalence Process Proteins Public Health Publishing Research Role Sampling Severity of illness Signal Transduction Synapses Temporal Lobe Testing Therapeutic Intervention Time Transfection alpha-bungarotoxin receptor cholinergic desensitization detection method exosome experimental study high throughput screening in vivo individual patient inhibitor interest knock-down molecular targeted therapies morris water maze mouse model neuron loss neurotoxic novel novel marker novel strategies object recognition pharmacologic premature prevent rapid detection receptor small hairpin RNA synergism tau-1 tool

项目摘要

Abstract Although interest has focused on crucial roles for amyloid beta and phosphorylated tau in pathogenesis of Alzheimer's disease (AD), an earlier and persistent hypothesis attributes cognitive impairment to loss of cholinergic signaling. We recently demonstrated that all these elements are linked by Ly6h, an endogenous inhibitor of Ca2+-permeable alpha7 nicotinic acetylcholine receptors (nAChRs). We found that amyloid beta reduces Ly6h, resulting in increased assembly of alpha7 nAChRs and thus a conversion of basal cholinergic to neurotoxic signaling. Importantly, we also found that Ly6h levels in temporal cortex and cerebrospinal fluid are inversely correlated with disease severity in AD patients. The present proposal seeks to complement these findings with related data in an animal model of AD. In particular, we will determine the degree to which lentiviral knockdown of Ly6h in the hippocampus exacerbates AD- driven increases in alpha7 nAChRs and phosphorylated tau. To correlate expected cellular effects with changes in hippocampal-dependent behaviors, we will also test for worsening of performance in Y-maze, Morris water maze and novel object recognition assays. We will also perform pharmacological experiments on neurons from AD model mice to extend our in vitro results, which suggest that Ly6h and alpha7 nAChRs reciprocally regulate each other, and that amyloid beta requires the open conformation of alpha7 to drive this process. Lastly, we will correlate Ly6h levels in CSF and exosomes with disease severity in individual patients, and we will develop a rapid ELISA assay to allow for related measurements to be made more routinely. Results from experiments in our proposal will thus provide an integrated overview about how Ly6h functions at a molecular, cellular and behavioral level to contribute to AD pathogenesis. At the same time our experiments will also provide valuable clinical data and a new tool that may aid in earlier diagnosis of AD.

摘要