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研究中心），与Selma Kanazir合作，配套补助金为R37 AG 023084，2004年9月15日， 8/31/2014.我们建议扩大同伴补助金的目的4，以研究热量饮食限制的影响 (DR)脑和全身清除阿尔茨海默病（AD）神经毒素淀粉样肽（A <$）和 认知功能使用AD样脑淀粉样变性的转基因模型。拟议的研究将 显著提高LMIC站点的神经科学研究能力，该站点是一个主要的生物医学中心。 研究机构在塞尔维亚和双方的LMIC合作者和下一代的能力 塞尔维亚研究人员将研究大脑疾病。LMIC站点具有DR模型方面的经验。DR减少A？ 病理和改善行为的小鼠AD样脑病理，但分子和细胞 这种改善的机制仍然难以捉摸。该提案的主要目标是确定 DR对（i）由固醇反应元件结合蛋白2介导的脑和全身A？清除的影响 （ii）SREBP 2/低密度脂蛋白受体相关蛋白1（LRP 1）和认知功能。LRP 1介导 脑血管系统、血液和肝脏中的A？清除是A？毒素清除的主要机制。 SREBP 2是调节胆固醇代谢的关键基因，是LRP 1的主要转录抑制因子。DR或 24小时禁食下调肝脏和大脑中的SREBP 2，并增加LRP 1表达，如 Kanazir的飞行员数据我们的中心假设是DR下调脑血管和肝脏中的SREBP 2， 这反过来又增加了LRP 1的活性，促进大脑和全身A？清除，从而改善认知能力。 功能协调发展的我们将研究正常饮食或DR（目的1）和强制SREBP 2表达的APPsw/0小鼠 由心肌蛋白基因转移到脑血管诱导（AIM 2）。将APPsw/0小鼠转移至 贝尔格莱德在2010年11月允许Kanazir开始她自己的殖民地。这是第一个建立的转基因菌落， 贝尔格莱德大学Kanazir小组的成员精通拟采用的方法 在LMIC的网站，并将继续接受培训，由兹洛科维奇的小组在新的国家的最先进的方法，根据需要。 在FIRCA提议之前，兹洛科维奇于1月份访问了卡纳齐尔及其在贝尔格莱德的团队成员 2010年8月4日至12月7日，Kanazir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。这项建议会 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 扩大大脑疾病的研究，引入新的技术方法，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互访 并帮助提高生产力，培养年轻的塞尔维亚研究人员的热情。我们预计 该提案将在Zlokovic小组和LMIC现场/PI小组之间建立长期合作关系。

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.