Role of LXR and ABCA1 in Abeta Aggregation and Toxicity

LXR 和 ABCA1 在 Abeta 聚集和毒性中的作用

• 批准号: 8197547
• 负责人: Nicholas Francis Fitz
• 金额: $ 5.39万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197547
• 关键词: ATP-Binding Cassette Transporters; Affect; Alleles; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Amyloid deposition; Apolipoprotein E; Apolipoproteins; Apolipoproteins A; Astrocytes; Binding; Biological Assay; Biological Models; Brain; Catabolism; Cholesterol; Cholesterol Homeostasis; Chronic; Cognition; Cognitive deficits; Conditioned Culture Media; Data; Detergents; Disease Progression; Engineering; Exhibits; Gene Targeting; Generations; Genes; Goals; Human; Impaired cognition; In Vitro; Knock-out; Late Onset Alzheimer Disease; Lead; Ligands; Lipids; Lipoproteins; Liver; Mediating; Mediator of activation protein; Memory; Molecular; Molecular Profiling; Mus; Pathogenesis; Pathology; Phenotype; Phospholipids; Plasma; Risk Factors; Rodent; Role; Route; Short-Term Memory; Staging; Structure; Testing; Toxic effect; Transgenic Mice; abeta accumulation; abeta toxicity; amyloid pathology; base; cholinergic; conditioned fear; density; disease phenotype; improved; in vitro Model; particle; receptor; research study; treatment effect; ATP-Binding Cassette Transporters; Affect; Alleles; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Amyloid deposition; Apolipoprotein E; Apolipoproteins; Apolipoproteins A; Astrocytes; Binding; Biological Assay; Biological Models; Brain; Catabolism; Cholesterol; Cholesterol Homeostasis; Chronic; Cognition; Cognitive deficits; Conditioned Culture Media; Data; Detergents; Disease Progression; Engineering; Exhibits; Gene Targeting; Generations; Genes; Goals; Human; Impaired cognition; In Vitro; Knock-out; Late Onset Alzheimer Disease; Lead; Ligands; Lipids; Lipoproteins; Liver; Mediating; Mediator of activation protein; Memory; Molecular; Molecular Profiling; Mus; Pathogenesis; Pathology; Phenotype; Phospholipids; Plasma; Risk Factors; Rodent; Role; Route; Short-Term Memory; Staging; Structure; Testing; Toxic effect; Transgenic Mice; abeta accumulation; abeta toxicity; amyloid pathology; base; cholinergic; conditioned fear; density; disease phenotype; improved; in vitro Model; particle; receptor; research study; treatment effect

DESCRIPTION (provided by applicant): The Abca1 and apolipoproteins regulate cholesterol and phospholipids efflux, and HDL formation. Abca1 ko mice exhibit decreased cholesterol efflux and poorly-lipidated ApoA-l and ApoE. Poor lipidation of apolipoproteins result in their increased catabolism. Recently, studies demonstrated that AD transgenic mice with engineered disruption of Abca1 have an increased level of amyloid deposition and cognitive impairments. LXR regulates the expression of Abca1 and ApoE both in humans and rodents. Treatment of AD transgenic mice with LXR ligands increases the expression of Abca1 and apolipoprotein. This could increase the lipidation of ApoE and ApoA-l which would lead to increased binding of A¿ to lipid-rich apolipoproteins, eventually decreasing its aggregation. Studies have shown diminished levels of insoluble A¿ and improved memory after short-term LXR ligand treatment of AD transgenic mice. The goals of this proposal are to demonstrate the role of Abca1 in toxicity and pathological aggregation of Ap and to emphasize the importance of Abca1 in the molecular pathogenesis of AD at a relatively early stage of the disease progression. We hypothesize that LXR ligand treatment will increase Abca1-regulated cholesterol efflux and generation of lipid-rich apolipoproteins that are critical mediators of A¿ pathology. Altogether the data will provide evidence that LXR treatment can slow AD progression and establish long-term LXR treatment effects. To test the hypothesis we will establish how LXR and Abca1 regulated lipidation of ApoE and ApoA-l influences A¿ aggregation. We will compare cholesterol and phospholipid content of lipid particles secreted in conditioned media of astrocytes derived from Abca1ko and WT mice treated with LXR ligands. Furthermore, we will determine how the lipidation states of ApoE and ApoA-l affect AP aggregation. In vitro studies will compare how LXR ligands affect AD phenotype and prove that this effect is mediated through Abca1. Comparing APP/Abca1wt and APP/Abca1ko mice treated with LXR ligands for 4 months will demonstrate that Abca1 is essential in mediating LXR effects on amyloid pathology and cognition and determine long-term treatment effects. Specifically, following LXR ligand treatment spatial working memory, reference memory, and fear conditioning will be examined. Cognitive decline will be correlated with amyloid pathology in the brain, cholinergic markers, and concentrations of ApoA-l and ApoE. Finally, based on results from gene array assays brain expression profiles in LXR treated mice will be assembled and correlated to the endpoints determined in the previous subaims. Better understanding the role of cholesterol metabolism in AD pathology will help develop new routes of treatment to slow disease progression.

描述（由适用提供）：ABCA1和载脂蛋白调节胆固醇和磷脂外排和HDL形成。 ABCA1 KO小鼠暴露于胆固醇外排降低，而降低的APOA-L和APOE。载脂蛋白的脂质不良导致它们的分解代谢增加。最近，研究表明，ABCA1工程破坏的AD转基因小鼠的淀粉样蛋白沉积和认知障碍水平增加。 LXR调节在人类和啮齿动物中的ABCA1和APOE的表达。用LXR配体治疗AD转基因小鼠会增加ABCA1和载脂蛋白的表达。这可能会增加APOE和APOA-L的脂化，这会导致A与富含脂质的载脂蛋白的结合增加，最终减少其聚集。研究表明，在短期LXR配体对AD转基因小鼠治疗后，不溶性A的水平降低，并改善了记忆力。该提案的目标是证明ABCA1在AP的毒性和病理聚集中的作用，并在疾病进展的相对早期阶段强调ABCA1在AD分子发病机理中的重要性。我们假设LXR配体治疗将增加ABCA1调节的胆固醇外排和富含脂质的载脂蛋白的产生，这些载脂蛋白是一种重要的病理学介质。总体数据将提供证据表明LXR治疗可以减缓AD的进展并建立长期LXR治疗效果。为了检验假设，我们将确定LXR和ABCA1如何调节APOE和APOA-L的脂质影响A聚集。我们将比较在用LXR配体处理的ABCA1KO和WT小鼠的星形胶质细胞中分泌的脂质颗粒的胆固醇和磷脂含量。此外，我们将确定APOE和APOA-L的脂质状态如何影响AP聚集。体外研究将比较LXR配体如何影响AD表型，并证明该作用是通过ABCA1介导的。比较用LXR配体治疗的APP/ABCA1WT和APP/ABCA1KO小鼠4个月，将证明ABCA1对于介导LXR对淀粉样蛋白病理学和认知的影响至关重要，并确定长期治疗效果。具体而言，将检查遵循LXR配体处理空间工作记忆，参考记忆和恐惧条件。认知能力下降将与大脑，胆碱能标记物以及APOA-L和APOE的浓度相关。最后，根据基因阵列的结果，在LXR处理的小鼠中，将组装并与先前子aim中确定的终点组装。更好地了解胆固醇代谢在AD病理学中的作用将有助于开发新的治疗途径以减缓疾病进展。