Caloric restriction and Alzheimers ABeta clearance pathway

描述（由申请人提供）：本研究将主要在塞尔维亚贝尔格莱德大学生物研究所（LMIC研究中心）与Selma Kanazir合作进行，伴随基金为R37 AG 023084，2004年9月15日至2014年8月31日。我们建议扩展同伴补助金的目标4，以研究热量饮食限制（DR）对阿尔茨海默病（AD）神经毒素淀粉样蛋白β-肽（A β）的脑和全身清除率的影响，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LMIC网站的神经科学研究能力，这是塞尔维亚的一个主要生物医学研究机构，以及LMIC合作者和下一代塞尔维亚研究人员研究大脑疾病的能力。LMIC站点具有DR模型方面的经验。DR减少了AD样脑病理小鼠的AD病理并改善了其行为，但这种改善的分子和细胞机制仍然难以捉摸。本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（SREBP 2）/低密度脂蛋白受体相关蛋白1（LRP 1）介导的脑和全身性Ablation清除率和（ii）认知功能的影响。LRP 1介导的脑血管系统、血液和肝脏中的黄芪清除是黄芪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的试验数据所示。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活性，促进脑和全身的ARF清除，从而改善认知功能。我们将研究正常饮食或DR的APPsw/0小鼠（目的1）和通过将心肌蛋白基因转移到脑血管诱导的强制SREBP 2表达的APPsw/0小鼠（目的2）。2010年11月，APPsw/0小鼠被转移到贝尔格莱德，让Kanazir开始自己的殖民地。这是贝尔格莱德大学建立的第一个转基因群体。Kanazir小组的成员熟悉拟在LMIC现场进行的拟议方法，并将继续接受Zlokovic小组的培训，根据需要采用最先进的新方法。在FIRCA提议之前，Zlokovic于2010年1月和6月在贝尔格莱德拜访了Kanazir及其团队成员，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度过了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。该提案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。这将使贝尔格莱德和洛杉矶之间的年轻研究人员能够进行短期互访，并有助于提高塞尔维亚年轻研究人员的生产力和培养他们的热情。我们预计该提案将在Zlokovic集团和LMIC网站/PI集团之间建立长期合作。

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 ß-peptide (Aß) and on cognitive functions using a transgenic model of AD-like cerebral ß-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 Aß 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 Aß 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 Aß clearance in the cerebrovascular system, blood and liver is the major mechanism for removal of Aß 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 Aß 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.