The Role of PPARgamma Activation in the Proteolytic Clearance of Abeta

PPARgamma 激活在 Abeta 蛋白水解清除中的作用

• 批准号: 7544649
• 负责人: Shweta Mandrekar
• 金额: $ 2.62万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7544649
• 关键词: ATP-Binding Cassette Transporters; Abeta clearance; Address; Affect; Agonist; Alzheimer' s Disease; Amino Acids; Amyloid beta-Protein; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoprotein E; Astrocytes; Brain; Characteristics; Cognition; Consensus; Data; Deposition; Disease; Disease Progression; Disruption; Endopeptidases; Energy Metabolism; Exhibits; Gene Expression; Gene Targeting; Genes; Glucose; Homeostasis; Hour; Human; Inflammatory; Insulinase; Laboratory Study; Lead; Length; Ligands; Lipids; Mediating; Molecular Chaperones; Molecular Conformation; Mus; Neprilysin; Nuclear Receptors; PPAR gamma; Pathogenesis; Pathology; Patients; Peptide Hydrolases; Peptides; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phase II Clinical Trials; Phase III Clinical Trials; Play; Production; Rate; Research Proposals; Role; Senile Plaques; Testing; Therapeutic; Work; activating transcription factor; amyloid precursor protein processing; extracellular; genetic risk factor; improved; interest; mouse model; peptide A; prevent; secretase; success

DESCRIPTION (provided by applicant): This research proposal is aimed at understanding the mechanisms through which the nuclear receptor, PPARgamma, acts to ameliorate Alzheimer's Disease (AD)related pathology in animal models and improves cognition in AD patients. PPARgamma is a ligand activated transcription factor whose activity is known to regulate glucose, lipid and energy metabolism. Importantly, it has also been shown to exhibit potent anti-inflammatory actions. Recent studies from this laboratory have shown that PPARgamma activation results in a reduction of plaque deposition, soluble Apound42 levels and inflammatory markers in V7171hAPP mice. Furthermore, PPARgamma activation results in the stimulation of Apound clearance from the medium. However, the underlying mechanism through which Abeta clearance is achieved is unknown. In the brain, A/?peptides are synthesized at high rates and are cleared at equally efficient rates. Any disruption in the production or clearance of Abeta can lead to its accumulation and depostion within the brain. Thus, we hypothesize that understanding mechanisms associated with Ay? clearance are of significance in slowing disease progression. In this proposal, we seek to elucidate mechanisms through which PPARgamma activation results in the degradation of soluble A/?species. We provide preliminary data that PPARgamma activation leads to the degradation of Apound and induces the expression of genes including ApoE and those that are responsible for its lipidation. We anticipate PPARgamma activation increases ApoE lipidation status by inducing the expression of LXR and its target genes ABCA1. Lipidated ApoE then acts to chaperone the proteolytic degradation of Abeta. This application is of particular interest because PPARgamma agonists are now being clinically evaluated for treatment of AD. Thus, it is of importance to understand the mechanisms through which PPARgamma exerts salutary effects on the degradation of soluble AB that may underly its therapeutic utility for disease treatment.

描述（由申请人提供）：该研究提案旨在了解核受体Ppargamma的机制，可改善动物模型中相关的阿尔茨海默氏病（AD）病理学并改善AD患者的认知。 Ppargamma是一种配体激活的转录因子，已知活性调节葡萄糖，脂质和能量代谢。重要的是，它也已显示出具有有效的抗炎作用。该实验室的最新研究表明，ppargamma激活导致V7171 -HAPP小鼠中斑块沉积，可溶性APOUND42水平和炎症标记的降低。此外，ppargamma激活会导致培养基刺激空白清除率。但是，实现Abeta清除率的基本机制尚不清楚。在大脑中，A/？肽以高速合成，并以同样有效的速率清除。 ABETA生产或清除的任何破坏都会导致其在大脑中的积累和解开。因此，我们假设理解与AY相关的机制？清除在减慢疾病进展方面具有重要意义。在此提案中，我们试图阐明ppargamma激活导致可溶性A/？物种降解的机制。我们提供了初步数据，即ppargamma激活会导致APOUND降解，并诱导包括APOE在内的基因的表达以及负责其脂化的基因。我们预计，ppargamma激活通过诱导LXR及其靶基因ABCA1的表达来增加APOE脂质的状态。然后，脂化的APOE作用于Abeta的蛋白水解降解。该应用特别令人感兴趣，因为现在正在对Ppargamma激动剂进行临床评估以进行AD治疗。因此，重要的是要了解ppargamma对可溶性AB降解的有益作用的机制，从而可能基本的疾病治疗治疗效用。