Caloric restriction and Alzheimers ABeta clearance pathway

描述(由申请人提供)：这项研究将主要在塞尔维亚贝尔格莱德大学生物研究所(LMIC网站)与Selma Kanazir合作进行，附带补助金为R37AG023084,2004年9月15日至2014年8月31日。我们建议扩展同伴资助的目标4，以研究热量饮食限制(DR)对大脑和系统清除阿尔茨海默病(AD)神经毒素淀粉样肽(A？)的影响，以及使用AD样脑淀粉样变性的转基因模型对认知功能的影响。拟议的研究将大大提高塞尔维亚主要生物医学研究机构LMIC站点的神经科学研究能力，以及LMIC合作者和下一代塞尔维亚研究人员研究大脑疾病的能力。LMIC网站拥有DR模型方面的经验。DR减少了AD样脑病理小鼠的A？病理，并改善了行为，但这种改善的分子和细胞机制仍然难以捉摸。这项建议的主要目的是确定DR对(I)由类固醇反应元件结合蛋白2(SREBP2)/低密度脂蛋白受体相关蛋白1(LRP1)介导的脑和系统A的清除以及(Ii)认知功能的影响。LRP1介导的A？在脑血管系统、血液和肝脏的清除是A？毒素清除的主要机制。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。Kanazir的试验数据显示，DR或禁食24小时可下调肝脏和大脑中SREBP2的表达，并增加LRP1的表达。我们的中心假设是DR下调了脑血管和肝脏中SREBP2的表达，进而增加了LRP1的活性，促进了大脑和全身的A？清除，从而改善了认知功能。我们将研究APPsw/0小鼠，在正常饮食或DR(目标1)和通过将myocardin基因转移到脑血管(目标2)诱导SREBP2强制表达的情况下。APPsw/0小鼠已于2010年11月被转移到贝尔格莱德，以便卡纳齐尔建立自己的殖民地。这是贝尔格莱德大学建立的第一个转基因群体。Kanazir小组的成员精通将在LMIC现场实施的拟议方法，并将根据需要继续接受Zlokovic小组关于新的最先进方法的培训。在FIRCA提议之前，Zlokovic于2010年1月至6月访问了贝尔格莱德的Kanazir和她的团队成员，Kanazir于2010年8月4日至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。这项提议将有助于贝尔格莱德大学建立急需的研究能力，使LMIC网站能够扩大对大脑疾病的研究，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的交流，并有助于提高生产率，并在年轻的塞尔维亚研究人员中建立热情。我们预计该提案将在Zlokovic集团和LMIC Site/PI‘s集团之间建立长期的合作关系。

DESCRIPTION (provided by applicant): 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.