Caloric restriction and Alzheimers ABeta clearance pathway

这项研究将主要在塞尔维亚贝尔格莱德大学生物研究所进行 (LMIC网站)与Selma Kanazir合作，附带赠款为R37AG023084,2004年9月15日至 2014年8月31日。我们建议延长配对补助金的目标4，以研究限制卡路里饮食的影响。 (DR)对阿尔茨海默病(AD)神经毒素淀粉样多肽(A)的脑和全身清除 使用AD样脑淀粉样变性转基因模型的认知功能。拟议的研究将 显著增强LMIC站点的神经科学研究能力，LMIC是主要的生物医学 塞尔维亚的研究机构以及LMIC合作者和下一代 塞尔维亚研究人员研究大脑紊乱。LMIC网站拥有DR模型方面的经验。DR降低了A？ 对类AD脑病变小鼠的病理和改善行为，但分子和细胞 这种改善的机制仍然难以捉摸。这项提案的主要目标是确定 类固醇反应元件结合蛋白2介导的DR(I)脑和系统A清除 低密度脂蛋白受体相关蛋白1(SREBP2)和(Ii)认知功能。LRP1介导的 脑血管系统、血液和肝脏的清除是清除A毒素的主要机制。 SREBP2是调节胆固醇代谢的关键基因，是LRP1的主要转录抑制因子。DR或 禁食24小时下调肝脏和大脑中SREBP2的表达，增加LRP1的表达，如 卡纳齐尔的飞行员数据。我们的中心假设是DR下调了脑血管和肝脏中SREBP2的表达 进而增加LRP1的活性，促进大脑和全身的A？清除，从而改善认知 功能。我们将研究APPsw/0小鼠，在正常饮食或DR(Aim 1)和强制表达SREBP2的情况下 通过将肌钙蛋白基因转移到脑血管来诱导(目标2)。APPsw/0小鼠已被转移到 2010年11月，贝尔格莱德允许卡纳齐尔建立自己的殖民地。这是在中国建立的第一个转基因群体 贝尔格莱德大学。Kanazir小组的成员精通要执行的拟议方法 在LMIC现场，Zlokovic的团队将继续根据需要接受最先进的新方法培训。 在FIRCA的提议之前，Zlokovic在1月份访问了Kanazir和她在贝尔格莱德的团队成员 和2010年6月，Kanazir从2010年8月4日到12月7日在Zlokovic位于罗切斯特的前实验室呆了4个月。 Kanazir为FIRCA的研究计划提供了创造性和重要的科学投入。这项提议将 通过启用LMIC网站，为贝尔格莱德大学建设急需的研究能力做出贡献 扩大对脑部疾病的研究，引进新的技术方法，并发展现有的 研究设施。它将使贝尔格莱德和洛杉矶之间的初级研究人员能够进行短期的互访 并帮助提高生产率，在年轻的塞尔维亚研究人员中建立热情。我们期待着 该提案将在Zlokovic集团和LMIC Site/PI‘s集团之间建立长期合作。

This research will be done primarily in Serbia at the Institute for Biological Research University of Belgrade (LMIC site) in collaboration with Selma Kanazir with the companion grant being R37AG023084, 9/15/2004 to 8/31/2014. We propose to extend aim 4 of the companion grant to study the effects of caloric dietary restriction (DR) on brain and systemic clearance of Alzheimer's disease (AD) neurotoxin amyloid ¿-peptide (A¿) and on cognitive functions using a transgenic model of AD-like cerebral ¿-amyloidosis. The proposed research will significantly enhance the neuroscience research capacity at the LMIC site which is a major biomedical research institution in Serbia and the capabilities of both the LMIC collaborator and the next generation of Serbian researchers to study brain disorders. The LMIC site has experience in DR models. DR reduces A¿ pathology and improves behavior in mice with AD-like cerebral pathology, but the molecular and cellular mechanisms of this improvement remain elusive. The major goal of this proposal is to determine the effects of DR on (i) brain and systemic A¿ clearance mediated by the sterol response element binding protein 2 (SREBP2)/low density lipoprotein receptor related protein 1 (LRP1) and (ii) cognitive functions. LRP1-mediated A¿ clearance in the cerebrovascular system, blood and liver is the major mechanism for removal of A¿ toxin. SREBP2, a key gene regulating cholesterol metabolism, is a major transcriptional suppressor of LRP1. DR or 24 h fasting downregulates SREBP2 in the liver and brain and increases LRP1 expression as shown by Kanazir's pilot data. Our central hypothesis is that DR downregulates SREBP2 in brain vasculature and liver which in turn increases LRP1 activity promoting brain and systemic A¿ clearance thereby improving cognitive functions. We will study APPsw/0 mice on normal diet or DR (aim 1) and with forced SREBP2 expression induced by myocardin gene transfer to brain blood vessels (aim 2). APPsw/0 mice have been transferred to Belgrade in Nov 2010 to allow Kanazir to start her own colony. This is the first transgenic colony established at the Belgrade University. Members of the Kanazir group are versed with the proposed methods to be performed at the LMIC site and will continue to be trained by Zlokovic's group in new state-of-the art methods as needed. Prior to the FIRCA proposal, Zlokovic visited Kanazir and members of her team in Belgrade during January and June 2010, and Kanazir spent 4 months in Zlokovic's former lab in Rochester from Aug 4 to Dec 7, 2010. Kanazir provided creative and important scientific input to the research plan of the FIRCA. This proposal will contribute to building much needed research capacity at the University of Belgrade by enabling the LMIC site to expand research in brain disorders, to introduce new technological approaches, and develop existing research facilities. It will enable short exchange visits of junior researchers between Belgrade and Los Angeles and help improve the productivity and build enthusiasm among young Serbian researchers. We expect the proposal will establish a long-standing collaboration between the Zlokovic group and the LMIC site/PI's group.