Mechanisms of regulation of amyloid-beta metabolism by CALHM1

CALHM1 调节淀粉样蛋白代谢的机制

基本信息

批准号：
8731789
负责人：
PHILIPPE MARAMBAUD
金额：
$ 34.54万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-15 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8731789
关键词：
APP-PS1 Adult Affect Age Aging-Related Process Alleles Alzheimer&apos s Disease Amyloid beta-Protein Amyloid deposition Atrophic Brain Brain Diseases C-terminal Calcium Calcium Channel Candidate Disease Gene Cell Culture System Cells Cellular biology Cerebral cortex Cerebrospinal Fluid Cerebrum Code Cognitive deficits Collaborations DNA Data Defect Deposition Development Disease Embryonic Development Event Gene Expression Profile Gene Expression Profiling Genes Goals Hippocampus (Brain)Homeostasis Human Immunohistochemistry Impairment In Vitro Insulin Insulin Receptor Insulinase Ion Channel Knock-out Knockout Mice Laboratories Literature Measurement Mediating Memory Memory impairment Metabolism Methods Mind Modeling Molecular Molecular Biology Mus Neurodegenerative Disorders Neurons Pathogenesis Pathologic Processes Peptide Hydrolases Phosphorylation Play Production Proteins Publishing Receptor Signaling Regulation Role Senile Plaques Signal Transduction Staining method Stains Synapses Testing Transcriptional Regulation Transgenic Mice Work activating transcription factor amyloid formation base beta-site APP cleaving enzyme 1 calcium metabolism cerebral atrophy conditioned fear genome-wide in vivo insight knockout animal morris water maze mouse model mutant neuron loss next generation sequencing novel object recognition peptide A prevent protein aggregate young adult

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by A¿ peptide deposition into cerebral senile plaques. CALHM1 is a recently identified neuronal calcium channel controlling AD age-at-onset and A¿ levels both in vitro in cell culture systems and in vivo in human cerebrospinal fluid (Dreses-Werringloer et al, Cell 2008; Koppel et al., Mol Med 2011). These results strongly support the notion that CALHM1, via an unknown mechanism, controls A¿ metabolism and AD pathogenesis. In order to gain insight into the mechanism by which CALHM1 controls A¿ metabolism, we recently generated a CALHM1 knockout (KO) mouse model. In these KO mice, we found that CALHM1 was required for the expression of insulin-degrading enzyme (IDE), a protease controlling A¿ clearance in vivo. Preliminary results also showed that CALHM1 KO mice have elevated levels of brain A¿ and develop significant deficits in memory formation. The long-term goal of this application is to test the working model that CALHM1 influences A¿ levels by controlling cerebral IDE expression, a mechanism that, when impaired, leads to A¿-dependent cognitive deficits in mice. In CALHM1 KO mice, we will first determine whether CALHM1 deficiency affects neuronal integrity and leads to amyloid deposition in the mouse brain. We will also determine the extent to which CALHM1 deficiency leads to A¿-dependent cognitive deficits in mice. Finally using cell and molecular biology methods, we will elucidate the molecular mechanism by which CALHM1 controls IDE expression.

描述（应用程序提供）：阿尔茨海默氏病（AD）是一种进行性神经退行性疾病，其特征是肽沉积到大脑老年斑块中。 CALHM1是一种最近鉴定出的神经元通道，可控制AD AD AT-AT-AT-AT-AT-AT-AT-AT-ANTEM in BELS培养系统和人体脑脊液中的体内（Fresses-Werringloer等，Cell，2008; Koppel et al。，Mol Med 2011）。这些结果强烈支持以下观点：CALHM1通过未知机制控制A代谢和AD发病机理。为了深入了解CALHM1控制A代谢的机制，我们最近生成了CALHM1敲除（KO）小鼠模型。在这些KO小鼠中，我们发现CALHM1是表达胰岛素降解酶（IDE）的表达所必需的，这是一种控制体内清除率的蛋白酶。初步结果还表明，CALHM1 KO小鼠的大脑A水平升高，并且在记忆形成中产生了重要的定义。该应用程序的长期目标是测试CALHM1通过控制脑IDE表达来影响A水平的工作模型，该机制在受损时会导致小鼠中依赖性的认知缺陷。在CALHM1 KO小鼠中，我们将首先确定CALHM1缺乏是否影响神经元的完整性并导致小鼠脑中的淀粉样蛋白沉积。我们还将确定CALHM1缺乏导致小鼠依赖性认知防御的程度。最后，使用细胞和分子生物学方法，我们将阐明 CALHM1控制IDE表达的分子机制。