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（由申请人提供）：阿尔茨海默病（AD）是一种进行性神经退行性疾病，其特征为 A¿ CALHM1 是最近发现的控制 AD 发病年龄和 A¿ 的神经元钙通道。细胞培养系统中的体外水平和人脑脊液中的体内水平（Dreses-Werringloer 等人，Cell 2008；Koppel 等人，Mol Med 2011）这些结果支持 CALHM1 通过未知机制控制 A 的观点。 ¿代谢和 AD 发病机制，以深入了解 CALHM1 控制 A¿我们最近构建了 CALHM1 敲除 (KO) 小鼠模型，在这些 KO 小鼠中，我们发现 CALHM1 是胰岛素降解酶 (IDE)（一种控制 A¿ 的蛋白酶）表达所必需的。初步结果还表明，CALHM1 KO 小鼠的脑 A¿ 水平升高。并在记忆形成中产生显着的缺陷该应用的长期目标是测试 CALHM1 影响 A¿ 的工作模型。通过控制大脑 IDE 表达来水平，这种机制在受损时会导致 A¿在 CALHM1 KO 小鼠中，我们将首先确定 CALHM1 缺陷是否会影响神经完整性并导致小鼠大脑中淀粉样蛋白沉积。我们还将确定 CALHM1 缺陷导致 A¿最后，我们将利用细胞和分子生物学方法来阐明小鼠的依赖性认知缺陷。 CALHM1 控制 IDE 表达的分子机制。