Mechanisms of regulation of amyloid-beta metabolism by CALHM1

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，其特征是a¿肽沉积到大脑老年斑中。CALHM1是最近发现的神经元钙通道，在体外细胞培养系统和体内人脑脊液中控制AD发病年龄和a¿水平（Dreses-Werringloer等人，cell 2008； Koppel等人，Mol Med 2011）。这些结果有力地支持了CALHM1通过一种未知机制控制A¿代谢和AD发病机制的观点。为了深入了解CALHM1控制A¿代谢的机制，我们最近建立了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）表达所必需的，IDE是一种控制体内a¿清除的蛋白酶。初步结果还显示，CALHM1 KO小鼠的大脑A¿水平升高，并在记忆形成方面出现显著缺陷。该应用程序的长期目标是测试CALHM1通过控制大脑IDE表达来影响A¿水平的工作模型，这种机制在受损时导致小鼠A¿依赖的认知缺陷。在CALHM1 KO小鼠中，我们将首先确定CALHM1缺乏是否会影响神经元完整性并导致小鼠脑内淀粉样蛋白沉积。我们还将确定CALHM1缺乏在多大程度上导致小鼠依赖A¿的认知缺陷。最后，我们将运用细胞和分子生物学的方法来阐明

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. PUBLIC HEALTH RELEVANCE: Alzheimer's disease is an incurable disorder of the brain characterized by the presence in the brain of protein aggregates called amyloid plaques. Recently, our group identified CALHM1 as a gene potentially involved in the pathological processes of the disease. The goal of this proposal is to elucidate the exact role played by CALHM1 in amyloid plaque formation and in the progression of Alzheimer's disease.