Peripheral & Brain Cholesterol Metabolism in Neurodegenerative Mouse Models
周边
基本信息
- 批准号:8700653
- 负责人:
- 金额:$ 9.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-04-01 至 2019-03-31
- 项目状态:已结题
- 来源:
- 关键词:ATP binding cassette transporter 1ATP-Binding Cassette TransportersAdenovirus VectorAffectAgeAgonistAllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease riskAmyloidApolipoprotein A-IApolipoprotein EApolipoproteinsApolipoproteins AAstrocytesBindingBlood VesselsBrainBrain imagingCellsCerebral Amyloid AngiopathyCholesterolCholesterol HomeostasisClinicalCognitionComplexDementiaDepositionDisease ProgressionEtiologyExcisionGeneticHigh Density LipoproteinsHomeostasisHumanImageImmunizationImpaired cognitionIn VitroKnock-in MouseKnock-outKnockout MiceLabelLate Onset Alzheimer DiseaseLearningLifeLinkLipidsLipoproteinsLiverMediatingMembrane Protein TrafficMicroscopyMinorityMolecular ChaperonesMusMutationNerve DegenerationNeurofibrillary TanglesNeuronsPathologyPeripheralPhenotypePredispositionProceduresProcessProductionProteinsRXRResearchRiskRisk FactorsRoleRouteSenile PlaquesSerumStructureTechniquesTherapeuticTimeTissuesToxic effectTrainingTransgenic MiceUp-RegulationViral VectorWomanamyloid pathologyamyloid precursor protein processingbaseclinically significantdesigngenetic risk factorhigh riskimprovedin vivoinsightmouse modelneuropathologyoverexpressionparticlepublic health relevancereceptorresponsible research conduct
项目摘要
Sporadic Alzheimer's disease (AD) is a late-onset dementia of unknown etiology, characterized by the
presence of amyloid b (A¿) containing senile plaques, neurofibrillary tangles, and cognitive decline.
Importantly, the inheritance of Apolipoprotein (APOE) ¿4 allele is the only established risk factor for sporadic
late onset AD. However, the mechanism underlying this association remains elusive. ATP binding cassette
transporter A1 (ABCA1) regulates cholesterol efflux from cells to cholesterol acceptors, primarily poorly
lipidated apolipoprotein A-I (APOA-I) and APOE thus generating nascent high density lipoprotein (HDL).
Disruption of Abca1 in APP expressing mice increased plaque levels in brain parenchyma and cerebral
amyloid angiopathy. Remarkably this was accompanied by abnormal HDL-like particle structure in the CSF
and decreased levels of APOA-I and APOE. Thus, processes that regulate APOE expression and lipidation
could affect its ability to influence brain A¿ homeostasis. In support of this hypothesis the lower level of APOE
in ¿4 carriers is associated with increased A¿ pathology and AD risk. Furthermore, stimulation of APOE
expression and lipidation with LXR and RXR agonists is associated with reduced A¿ pathology and improved
cognition in AD mouse models. The central hypothesis is that Abca1 affects A¿ formation/deposition and
clearance, through lipidation of ApoE and formation of HDL, therefore therapeutic approaches which
affect the levels of Abca1 and ApoE can be used to treat the A¿ pathology. To prove the hypothesis we
use viral vectors to overexpress apolipoproteins and multiphoton microscopy to assess in vivo the effects on
A¿ pathology and neuronal abnormalities in APP transgenic mice. Furthermore, we will characterize the
effects of a clinically significant mutation of ABCA1 on APP mouse model phenotype. Lastly, we will examine
how changes in peripheral and central expression of Abca1 affect lipid profiles and amyloid levels. The
completion of this proposal will have a significant impact on our understanding of how different APOE alleles
and a clinical relevant mutation of ABCA1 effects amyloid pathology. The design will allow for much more
insight into a possible mechanism by which APOE affects AD progression. Furthermore, the proposal will
further our understanding of the importance of central and peripheral ABCA1 in brain lipid profiles and amyloid
levels, allowing for improved treatment targets.
散发性阿尔茨海默病(AD)是一种病因不明的晚发性痴呆,其特征是
存在含有老年斑的淀粉样蛋白b(A)、神经原纤维缠结和认知功能减退。
重要的是,载脂蛋白(ApoE)?4等位基因的遗传是唯一确定的散发性危险因素。
晚发性阿尔茨海默病。然而,这种联系背后的机制仍然难以捉摸。三磷酸腺苷结合盒
转运蛋白A1(ABCA1)调节胆固醇从细胞到胆固醇受体的外流,主要是很差的
脂化载脂蛋白A-I(apoA-I)和载脂蛋白E,从而产生新生高密度脂蛋白(HDL)。
APP表达小鼠ABCA1基因缺失可增加脑实质和脑组织斑块水平
淀粉样血管病。值得注意的是,伴随着脑脊液中异常的高密度脂蛋白样颗粒结构
并降低载脂蛋白A-I和载脂蛋白E水平。因此,调节载脂蛋白E表达和脂化的过程
可能会影响它影响大脑A?动态平衡的能力。为了支持这一假设,载脂蛋白E的较低水平
4名携带者与A病理和AD风险增加相关。此外,对APOE的刺激
LXR和RXR激动剂的表达和脂化与A?病理降低和改善相关
阿尔茨海默病小鼠模型的认知。中心假设是ABCA1影响A?的形成/沉积和
通过脂化载脂蛋白E和形成高密度脂蛋白清除,因此治疗方法
影响ABCA1和ApoE水平可用于治疗A?病理。为了证明这一假设,我们
用病毒载体过表达载脂蛋白和多光子显微镜在体内评估对
APP转基因小鼠的病理和神经元异常。此外,我们还将描述
临床显著的ABCA1突变对APP小鼠模型表型的影响。最后,我们将研究
ABCA1外周和中枢表达的变化如何影响脂类和淀粉样蛋白水平。这个
这一提议的完成将对我们理解不同的载脂蛋白E等位基因
ABCA1的一个临床相关突变会影响淀粉样蛋白的病理改变。这一设计将考虑到更多
深入了解载脂蛋白E影响AD进展的可能机制。此外,该提案将
进一步了解中枢和外周ABCA1在脑脂类和淀粉样蛋白中的重要性
水平,从而改善治疗目标。
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:
$ 9.26万 - 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:
$ 9.26万 - 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:
$ 9.26万 - 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:
$ 9.26万 - 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:
$ 9.26万 - 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:
7982008 - 财政年份:2009
- 资助金额:
$ 9.26万 - 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
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8197547 - 财政年份:2009
- 资助金额:
$ 9.26万 - 项目类别:
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