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）：这项研究将主要在塞尔维亚贝尔格莱德生物研究所（LMIC 站点）与 Selma Kanazir 合作进行，配套资助为 R37AG023084，2004 年 9 月 15 日至 8 月 31 日2014 年。我们建议扩展配套赠款的目标 4，以研究热量饮食限制 (DR) 对阿尔茨海默病大脑和全身清除的影响(AD) 神经毒素淀粉样β-肽 (Aß) 以及使用 AD 样脑β-淀粉样变性转基因模型对认知功能的影响。拟议的研究将显着增强 LMIC 站点的神经科学研究能力，该中心是一个主要的生物医学研究机构。塞尔维亚以及 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有所下降 LMIC 站点在 DR Aß 病理学方面拥有丰富的经验，并改善了 AD 样小鼠的行为。脑病理学，但这种改善的分子和细胞机制仍然难以捉摸，该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)/ 介导的大脑和全身 Aß 清除的影响。低密度脂蛋白受体相关蛋白 1 (LRP1) 和 (ii) LRP1 介导的脑血管系统、血液和肝脏中的 Aß 清除是清除 Aß 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，如 Kanazir 的试验数据所示，DR 或 24 小时禁食会下调肝脏和大脑中的 SREBP2，并增加 LRP1 的表达。血管系统和肝脏，进而增加 LRP1 活性，促进大脑和全身 Aß，从而改善认知功能。我们将研究 APPsw/0 小鼠的认知功能。正常饮食或 DR（目标 1）以及通过心肌素基因转移至脑血管诱导的强制 SREBP2 表达（目标 2）的 APPsw/0 小鼠已于 2010 年 11 月转移到贝尔格莱德，以便卡纳齐尔开始她自己的群体。卡纳齐尔小组的成员熟悉在 LMIC 地点实施的拟议方法，并将继续接受兹洛科维奇的培训。在 FIRCA 提案之前，Zlokovic 于 2010 年 1 月至 6 月期间在贝尔格莱德拜访了 Kanazir 及其团队成员，并于 8 月 4 日至 8 月 11 日在 Zlokovic 位于罗彻斯特的前实验室待了 4 个月。 2010 年 12 月 7 日。卡纳齐尔为 FIRCA 的研究计划提供了创造性和重要的科学投入。该提案将通过启用贝尔格莱德大学急需的研究能力做出贡献。 LMIC 站点将扩大脑部疾病的研究，引入新技术方法，并开发现有的研究设施，这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交流，并有助于提高塞尔维亚年轻研究人员的生产力和热情。该提案将在 Zlokovic 小组和 LMIC 站点/PI 小组之间建立长期合作关系。

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