LXR and PPARgamma mediated Abeta clearance mechanisms

LXR 和 PPARgamma 介导的 Abeta 清除机制

基本信息

批准号：
7493420
负责人：
GARY E. LANDRETH
金额：
$ 31.04万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-15 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7493420
关键词：
1 year old ATP-Binding Cassette Transporters Abeta clearance Affect Affinity Age Agonist Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Animal Model Apolipoprotein E Apolipoproteins Astrocytes Attenuated Back Binding Blood Circulation Brain Cholesterol Cognition Complex Data Deposition Development Disease Endopeptidases Exhibits GW 3965 Gene Targeting Genes High Density Lipoproteins Insulinase Late Onset Alzheimer Disease Ligands Link Lipids Liver Mediating Membrane Metabolism Microglia Molecular Molecular Chaperones Mus Neprilysin Nuclear Receptors PPAR gamma Pathogenesis Pathology Peptide Hydrolases Peptides Peripheral Peroxisome Proliferator-Activated Receptors Phospholipids Process Protein Isoforms Protein Overexpression Proteolysis Receptor Activation Reporting Research Personnel Resistance Risk Role Secondary to Testing Tg2576 Therapeutic Therapeutic Agents Time activating transcription factor aging brain apolipoprotein E-4 cholesterol trafficking extracellular feeding interest lipid metabolism neuron loss novel novel therapeutics particle peptide A prevent receptor receptor function scaffold synaptic function therapeutic target trafficking

项目摘要

DESCRIPTION (provided by applicant): This application is focused on the development of new therapeutic approaches to Alzheimer's disease (AD) that target the nuclear receptors, liver X receptors (LXRs) and peroxisome proliferator-activated receptor gamma (PPARy). We demonstrate that treatment of an aged animal model of AD (Tg2576) with LXR agonists results in the reduction of A¿ peptide levels and plaque load. We show that the ability of LXR agonists to clear A¿ from the brain is reliant upon ApoE. Importantly, we demonstrate an entirely novel mechanism through which ApoE facilitates the proteolytic degradation of A¿ peptides. LXR activation results in the transcriptional induction of ApoE and the lipid transporter ABCA1. ABCA1 is required for the functional maturation of ApoE through its lipidation, leading to the formation of ApoE-containing HDL-like particles that are required for cholesterol and phospholipid trafficking in the brain. A¿ binds to ApoE with high affinity and this interaction is governed by the lipidation status of ApoE. We show that lipidated forms of ApoE facilitate the intracellular degradation of A¿ peptides by microglia through neprilysin- dependent proteolysis. Further, we demonstrate that the lipidated ApoE acts to chaperone the extracellular degradation of A¿ by insulin degrading enzyme. In contrast, poorly lipidated forms of ApoE form stable, protease resistant complexes. Importantly, agonists of the related nuclear receptor PPARy can elicit similar effects and we hypothesize that PPARy participates in a positive, self reinforcing, feed back loop with LXR to stimulate ApoE lipidation and A¿ clearance. These data establish a previously unrecognized action of ApoE, facilitating the proteolytic clearance of A¿ from the brain that may underlie its participation in AD pathogenesis. We propose to establish the therapeutic parameters for LXR agonist treatment to prevent and to reverse the development of AD-related plaque pathology in an animal model of AD. We will validate the LXRs as a therapeutic target by examination of murine models of AD in which LXRs have been genetically inactivated. We will establish the mechanisms through which the LXRs and PPARy target genes, most prominently ApoE and ABCA1, to facilitate A¿ clearance. We will test if the actions of PPARy on A¿ clearance are secondary to, and reliant upon, LXR function.

描述（由应用提供）：该应用集中在针对靶向核受体，肝X受体（LXR）和过氧化物体增殖物激活受体伽马（PPARY）的新的治疗方法（AD）的开发。我们证明，用LXR激动剂对AD的老化动物模型（TG2576）的处理导致A肽水平和斑块负荷的降低。我们表明，LXR激动剂从大脑中清除A字的能力依赖于APOE。重要的是，我们展示了一种完全新颖的机制，通过该机制，APOE通过该机制准备了肽的蛋白水解降解。 LXR激活导致APOE和脂质转运蛋白ABCA1的转录诱导。 ABCA1通过其脂质化的功能成熟是必需的，从而导致形成含有APOE的HDL样颗粒，这是胆固醇和磷脂在大脑中所需的所需的。 A与APOE结合具有高亲和力，这种相互作用受APOE的脂质状态的控制。我们表明，APOE的脂化形式通过小胶质细胞通过Neprilysin-依赖性蛋白水解制备了小胶质细胞A肽的细胞内降解。此外，我们证明了脂质的APOE作用于通过胰岛素降解酶伴侣伴侣的细胞外降解。相比之下，ApoE的脂化形式不良形成稳定的抗蛋白酶抗复合物。重要的是，相关核接收器的激动剂可以引起类似的效果，我们假设Ppary参与了带有LXR的积极的，自我加强，向后循环以刺激ApoE脂质化和A级清除率。这些数据建立了APOE的先前未识别的作用，支持大脑的蛋白水解清除率，这可能是其参与AD发病机理的基础。我们建议建立用于LXR激动剂治疗的治疗参数，以预防和扭转AD动物模型中与AD相关的斑块病理学的发展。我们将通过检查LXR在遗传失活的AD的鼠模型中验证LXR作为治疗靶标。我们将建立LXR和PPARY靶基因（最突出的APOE和ABCA1）促进清除率的机制。我们将测试PPARY对清除率的作用是否是次要的，并依赖于LXR功能。