Caloric restriction and Alzheimers ABeta clearance pathway

热量限制和阿尔茨海默病 Aβ 清除途径

• 批准号: 8897941
• 负责人: Berislav V Zlokovic
• 金额: $ 5.79万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8897941
• 关键词: Abeta clearance; Advanced Glycosylation End Products; Age-Months; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloidosis; Arteries; Behavior; Binding; Binding Proteins; Biomedical Research; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Diseases; Caloric Restriction; Cerebral Amyloid Angiopathy; Cerebrovascular system; Cerebrum; Cholesterol; Cholesterol Homeostasis; Chronic; Cognition; Collaborations; Companions; Data; Diet; Endothelium; Excision; Fasting; Gene Transfer; Generations; Genes; Goals; Grant; Health; Hepatic; Homeobox Genes; Human; Institutes; Institution; Iowa; Kidney; LDL-Receptor Related Protein 1; LDL-Receptor Related Protein 2; Lipoprotein Receptor; Liver; Los Angeles; Mediating; Mesenchyme; Methods; Modeling; Mus; Mutation; Neurosciences; Neurosciences Research; Neurotoxins; Pathology; Pathway interactions; Pericytes; Peripheral; Plasma; Productivity; Proteins; Reporting; Research; Research Personnel; Response Elements; Scientist; Serbia; Serum Response Factor; Site; Smooth Muscle Myocytes; Sterols; Study of serum; Synapses; Talents; Testing; Toxin; Training; Transgenes; Transgenic Mice; Transgenic Organisms; Universities; Visit; amyloid peptide; base; biological research; cerebrovascular; cognitive function; dietary restriction; experience; feeding; improved; member; mind control; molecular pathology; myocardin; new therapeutic target; next generation; peptide A; prevent; receptor; research facility; skills; transgenic model of alzheimer disease

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.

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站点）进行，与Selma Kanazir合作，配套资助为R37AG023084, 2004年9月15日至2014年8月31日。我们建议扩展伴随拨款的目标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ß-肽（asß）的大脑和全身清除的影响，以及使用AD样大脑ß-淀粉样变性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，LMIC网站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站点具有容灾模型的经验。DR减少了ad样脑病理小鼠的asb病理并改善了行为，但这种改善的分子和细胞机制尚不清楚。本提案的主要目标是确定DR对(i)由甾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）介导的脑和全身阿斯丁清除和（ii）认知功能的影响。lrp1介导的阿斯汀在脑血管系统、血液和肝脏中的清除是阿斯汀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的主要转录抑制基因。根据Kanazir的先导数据显示，DR或禁食24小时可下调肝脏和大脑中的SREBP2，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的SREBP2，这反过来又增加了LRP1的活性，促进了大脑和全身的阿斯丁清除，从而改善了认知功能。我们将研究正常饮食或DR的APPsw/0小鼠（目的1）和心肌素基因转移到脑血管诱导SREBP2表达的小鼠（目的2）。APPsw/0小鼠已于2010年11月转移到贝尔格莱德，让Kanazir开始自己的种群。这是在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现场执行的拟议方法，并将根据需要继续由Zlokovic小组培训最新的最先进方法。在FIRCA提案之前，Zlokovic于2010年1月和6月在贝尔格莱德拜访了Kanazir和她的团队成员，Kanazir从2010年8月4日到12月7日在Zlokovic以前在罗切斯特的实验室呆了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。这一建议将有助于贝尔格莱德大学建立急需的研究能力，使LMIC站点能够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。我们期望该提案将建立Zlokovic集团和LMIC网站/PI集团之间的长期合作。

项目成果

Expression profiles of cholesterol metabolism-related genes are altered during development of experimental autoimmune encephalomyelitis in the rat spinal cord.

• DOI: 10.1038/s41598-017-02638-8
• 发表时间: 2017-06-02
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Lavrnja I;Smiljanic K;Savic D;Mladenovic-Djordjevic A;Tesovic K;Kanazir S;Pekovic S
• 通讯作者: Pekovic S

Pharmacological intervention in a transgenic mouse model improves Alzheimer's-associated pathological phenotype: Involvement of proteasome activation.

• DOI: 10.1016/j.freeradbiomed.2020.11.038
• 发表时间: 2021-01
• 期刊: Free radical biology & medicine
• 影响因子: 7.4
• 作者: Mladenovic Djordjevic AN;Kapetanou M;Loncarevic-Vasiljkovic N;Todorovic S;Athanasopoulou S;Jovic M;Prvulovic M;Taoufik E;Matsas R;Kanazir S;Gonos ES
• 通讯作者: Gonos ES

Long-term dietary restriction differentially affects the expression of BDNF and its receptors in the cortex and hippocampus of middle-aged and aged male rats.

长期饮食限制对中老年雄性大鼠皮质和海马BDNF及其受体表达的影响存在差异。

• DOI: 10.1007/s10522-014-9537-9
• 发表时间: 2015
• 期刊: Biogerontology
• 影响因子: 4.5
• 作者: Smiljanic,Kosara;Pesic,Vesna;MladenovicDjordjevic,Aleksandra;Pavkovic,Zeljko;Brkic,Marjana;Ruzdijic,Sabera;Kanazir,Selma
• 通讯作者: Kanazir,Selma