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

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（由申请人提供）：Abca1 和载脂蛋白调节胆固醇和磷脂流出，Abca1 ko 小鼠表现出胆固醇流出和脂化不良，载脂蛋白脂化不良导致其分解代谢增加。研究表明，Abca1 基因工程破坏的 AD 转基因小鼠的淀粉样蛋白沉积水平增加，认知障碍也增加。 LXR 调节人类和啮齿动物中 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，从而导致 A¿研究表明，不溶性 A 的水平降低。短期LXR配体治疗AD转基因小鼠后记忆力得到改善 本提案的目的是证明Abca1在Ap的毒性和病理聚集中的作用，并从相对的角度强调Abca1在AD分子发病机制中的重要性。我们追求 LXR 配体治疗将增加 Abca1 调节的胆固醇流出和富含脂质的载脂蛋白的产生，这是 A¿总而言之，这些数据将提供证据表明 LXR 治疗可以减缓 AD 进展并建立长期 LXR 治疗效果。我们将比较来自用 LXR 配体处理的 Abca1ko 和 WT 小鼠的条件培养基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 的脂化状态如何影响体外 AP 聚集。研究将比较 LXR 配体如何影响 AD 表型，并证明这种效应是通过比较 APP/Abca1wt 和 Abca1 介导的。使用 LXR 配体治疗 4 个月的 APP/Abca1ko 小鼠将证明 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，并在 LXR 配体治疗空间工作记忆、参考记忆和恐惧调节后确定长期治疗效果。最后，基于基因阵列检测的结果，认知能力下降将与大脑中的淀粉样蛋白病理、胆碱能标记物以及 ApoA-1 和 ApoE 的浓度相关。 LXR 治疗小鼠的大脑表达谱将被组装并与先前子目标中确定的终点相关联，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。

项目成果

Genome-wide approaches reveal EGR1-controlled regulatory networks associated with neurodegeneration.

• DOI: 10.1016/j.nbd.2013.11.005
• 发表时间: 2014-03
• 期刊: NEUROBIOLOGY OF DISEASE
• 影响因子: 6.1
• 作者: Koldamova, Radosveta;Schug, Jonathan;Lefterova, Martina;Cronican, Andrea A.;Fitz, Nicholas F.;Davenport, Faith A.;Carter, Alexis;Castranio, Emilie L.;Lefterov, Iliya
• 通讯作者: Lefterov, Iliya

Genome-wide alteration of histone H3K9 acetylation pattern in mouse offspring prenatally exposed to arsenic.

• DOI: 10.1371/journal.pone.0053478
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Cronican AA;Fitz NF;Carter A;Saleem M;Shiva S;Barchowsky A;Koldamova R;Schug J;Lefterov I
• 通讯作者: Lefterov I

Comment on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models".

• DOI: 10.1126/science.1235809
• 发表时间: 2013-05-24
• 期刊: Science (New York, N.Y.)
• 作者: Fitz NF;Cronican AA;Lefterov I;Koldamova R
• 通讯作者: Koldamova R