Role of LXR and ABCA1 in Abeta Aggregation and Toxicity
LXR 和 ABCA1 在 Abeta 聚集和毒性中的作用
基本信息
- 批准号:7982008
- 负责人:
- 金额:$ 5.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:ATP-Binding Cassette TransportersAffectAllelesAlzheimer&aposs DiseaseAmyloid beta-Protein PrecursorAmyloid depositionApolipoprotein EApolipoproteinsApolipoproteins AAstrocytesBindingBiological AssayBiological ModelsBrainCatabolismCholesterolCholesterol HomeostasisChronicCognitionCognitive deficitsConditioned Culture MediaDataDetergentsDisease ProgressionEngineeringExhibitsGene TargetingGenerationsGenesGoalsHumanImpaired cognitionIn VitroKnock-outLate Onset Alzheimer DiseaseLeadLigandsLipidsLipoproteinsLiverMediatingMediator of activation proteinMemoryMolecularMolecular ProfilingMusPathogenesisPathologyPhenotypePhospholipidsPlasmaRisk FactorsRodentRoleRouteShort-Term MemoryStagingStructureTestingToxic effectTransgenic Miceabeta accumulationabeta toxicityamyloid pathologybasecholinergicconditioned feardensitydisease phenotypeimprovedin vitro Modelparticlereceptorresearch studytreatment effect
项目摘要
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):Abca 1和载脂蛋白调节胆固醇和磷脂流出以及HDL形成。Abca 1 ko小鼠表现出胆固醇流出减少和脂化不良的ApoA-I和ApoE。载脂蛋白脂化不良导致其催化活性增加。最近,研究表明,工程破坏Abca 1的AD转基因小鼠具有增加的淀粉样蛋白沉积和认知障碍水平。LXR调节人类和啮齿动物中Abca 1和ApoE的表达。用LXR配体治疗AD转基因小鼠增加Abca 1和载脂蛋白的表达。这可能增加ApoE和ApoA-I的脂化,这将导致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,AD转基因小鼠短期LXR配体治疗后,不溶性A?水平降低,记忆力改善。本提案的目的是证明Abca 1在Ap的毒性和病理聚集中的作用,并强调Abca 1在疾病进展的相对早期阶段在AD的分子发病机制中的重要性。我们假设LXR配体治疗将增加Abca 1调节的胆固醇流出和富含脂质的载脂蛋白的产生,这些载脂蛋白是A ²病理学的关键介质。总之,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。为了验证这一假设,我们将确定LXR和Abca 1如何调节ApoE的脂化,以及ApoA-I如何影响A?聚集。我们将比较LXR配体处理的Abca 1 ko和WT小鼠星形胶质细胞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-I的脂化状态如何影响AP聚集。体外研究将比较LXR配体如何影响AD表型,并证明这种作用是通过Abca 1介导的。比较用LXR配体治疗4个月的APP/Abca 1 wt和APP/Abca 1 ko小鼠,将证明Abca 1在介导LXR对淀粉样蛋白病理学和认知的作用中是必不可少的,并确定长期治疗效果。具体地,在LXR配体处理后,将检查空间工作记忆、参考记忆和恐惧条件反射。认知下降将与脑中的淀粉样蛋白病理学、胆碱能标志物以及ApoA-I和ApoE的浓度相关。最后,基于基因阵列测定的结果,将收集LXR处理小鼠的脑表达谱,并将其与先前子目标中确定的终点相关。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来减缓疾病进展。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Nicholas Francis Fitz其他文献
Nicholas Francis Fitz的其他文献
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{{ truncateString('Nicholas Francis Fitz', 18)}}的其他基金
Neurodevelopmental and neurodegenerative effects of environmental determinants: altering neural cellular populations impacting homeostatic functions and inflammatory response.
环境决定因素的神经发育和神经退行性影响:改变影响稳态功能和炎症反应的神经细胞群。
- 批准号:
10612071 - 财政年份:2021
- 资助金额:
$ 5.13万 - 项目类别:
Neurodevelopmental and neurodegenerative effects of environmental determinants: altering neural cellular populations impacting homeostatic functions and inflammatory response.
环境决定因素的神经发育和神经退行性影响:改变影响稳态功能和炎症反应的神经细胞群。
- 批准号:
10463541 - 财政年份:2021
- 资助金额:
$ 5.13万 - 项目类别:
Peripheral & Brain Cholesterol Metabolism in Neurodegenerative Mouse Models
周边
- 批准号:
8828055 - 财政年份:2014
- 资助金额:
$ 5.13万 - 项目类别:
Peripheral & Brain Cholesterol Metabolism in Neurodegenerative Mouse Models
周边
- 批准号:
9249458 - 财政年份:2014
- 资助金额:
$ 5.13万 - 项目类别:
Peripheral & Brain Cholesterol Metabolism in Neurodegenerative Mouse Models
周边
- 批准号:
8700653 - 财政年份:2014
- 资助金额:
$ 5.13万 - 项目类别:
Peripheral & Brain Cholesterol Metabolism in Neurodegenerative Mouse Models
周边
- 批准号:
9041470 - 财政年份:2014
- 资助金额:
$ 5.13万 - 项目类别:
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 - 财政年份:2009
- 资助金额:
$ 5.13万 - 项目类别:
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