Understanding the Origins of Amyloid Deposition in Cerebral Amyloid Angiopathy
了解脑淀粉样血管病中淀粉样蛋白沉积的起源
基本信息
- 批准号:9919003
- 负责人:
- 金额:$ 38.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-10-01 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdoptedAllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease patientAmyloidAmyloid FibrilsAmyloid beta-42Amyloid beta-ProteinAmyloid depositionBindingBiological MarkersBlood VesselsBrainCerebral Amyloid AngiopathyCerebrovascular systemChronicChronologyDementiaDepositionDevelopmentDiseaseEnvironmentFamilial Cerebral Amyloid AngiopathyFamilial diseaseFutureGangliosidesGoalsHemorrhageHumanIn VitroInflammationInvestigationIowaIschemiaKnowledgeLaboratoriesMembraneMutationNMR SpectroscopyNaturePathogenesisPathologicPatientsPeptidesPrevalenceProcessProductionProtein PrecursorsProteinsResearchSamplingSeedsSenile PlaquesSpectroscopy, Fourier Transform InfraredSporadic Cerebral Amyloid AngiopathyStructureSystemTransgenic MiceVariantVascular Cognitive Impairmentabeta accumulationamyloid formationamyloid pathologyamyloid structurebrain parenchymabrain tissuecerebrovascularcomorbiditydiagnostic biomarkerearly onseteffective therapyhuman diseasehypoperfusionmembrane modelmonomermouse modelmutantnovel therapeutic interventionpreferenceprotein aminoacid sequencepublic health relevancevascular cognitive impairment and dementia
项目摘要
DESCRIPTION (provided by applicant): Cerebrovascular accumulation of the amyloid ß-protein (Aß), a condition known as cerebral amyloid angiopathy (CAA), is an important driver of vascular cognitive impairment and dementia (VCID) and is a common comorbidity of patients with Alzheimer's disease (AD). CAA can promote VCID through a number of mechanisms including chronic inflammation, hypoperfusion and ischemia, loss of vessel wall integrity and hemorrhage. In addition to its prevalence in AD, several related familial CAA disorders result from specific mutations that reside within the Aß peptide sequence of the Aß precursor protein including the Dutch-type (E22Q) and Iowa-type (D23N) mutations. Despite the highly fibrillogenic nature of Dutch mutant and Iowa mutant Aß peptides, fibrillar Aß is restricted to te cerebral vasculature in these familial disorders. Recent evidence suggests the cerebral vascular amyloid is distinct from parenchymal plaque amyloid. However, there is a poor understanding as to why cerebral vascular amyloid forms and its unique structural features that promotes distinct pathological consequences leading to VCID. Thus, the focus of this proposal is to fill this critica void in knowledge. Accordingly, the overall hypothesis of this proposal is that fibrillar amyloid i cerebral blood vessels possesses distinct structural features compared to parenchymal fibrillar amyloid and unique anti-parallel structures, enhanced by CAA mutations, drives the cerebral vascular specific deposition of amyloid in brain. To address this hypothesis we propose three specific aims. First, we will determine the structure, assembly and membrane interactions of wild-type and the Dutch and Iowa CAA mutants of Aß in solution and model membrane systems that drive their compartmental deposition. Second, we will determine how familial CAA variants of Aß chronologically influence the structural features and assembly of wild-type Aß in the brains of transgenic mice. Third, we will isolate parenchymal plaque amyloid and cerebral vascular amyloid from post mortem brain tissue of AD cases, sporadic CAA cases and familial CAA cases and investigate their ability to promote assembly of wild-type and CAA mutant Aß peptides. These important studies will reveal the distinct structural signatures of cerebral vascular and parenchymal plaque amyloid deposits in human disease. Presently, there are no reliable biomarkers or effective therapies specifically for CAA and VCID. These deficiencies are complicated by our lack of understanding of the unique structural attributes of cerebral vascular amyloid and its early-stage oligomeric precursors, and their distinctive features and processes compared to parenchymal plaque amyloid. The present proposal will seek to fill this critical void in our knowledge and will advance our understanding of the pathogenesis of CAA and provide the basis for the future development of novel therapeutic interventions and diagnostic markers for CAA and VCID.
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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STEVEN Owen SMITH其他文献
STEVEN Owen SMITH的其他文献
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{{ truncateString('STEVEN Owen SMITH', 18)}}的其他基金
Structural Identification and Functional Consequences of Different Amyloid Strains in Alzheimer's Disease
阿尔茨海默病中不同淀粉样蛋白菌株的结构鉴定和功能后果
- 批准号:
9672144 - 财政年份:2018
- 资助金额:
$ 38.38万 - 项目类别:
Structural Identification and Functional Consequences of Different Amyloid Strains in Alzheimer's Disease
阿尔茨海默病中不同淀粉样蛋白菌株的结构鉴定和功能后果
- 批准号:
10405031 - 财政年份:2018
- 资助金额:
$ 38.38万 - 项目类别:
Structural Identification and Functional Consequences of Different Amyloid Strains in Alzheimer's Disease
阿尔茨海默病中不同淀粉样蛋白菌株的结构鉴定和功能后果
- 批准号:
9789805 - 财政年份:2018
- 资助金额:
$ 38.38万 - 项目类别:
Structural Identification and Functional Consequences of Different Amyloid Strains in Alzheimer's Disease
阿尔茨海默病中不同淀粉样蛋白菌株的结构鉴定和功能后果
- 批准号:
10176329 - 财政年份:2018
- 资助金额:
$ 38.38万 - 项目类别:
Understanding the Origins of Amyloid Deposition in Cerebral Amyloid Angiopathy
了解脑淀粉样血管病中淀粉样蛋白沉积的起源
- 批准号:
9251922 - 财政年份:2016
- 资助金额:
$ 38.38万 - 项目类别:
Mechanism of inhibition of APP processing and amyloid formation
APP 加工和淀粉样蛋白形成的抑制机制
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8332308 - 财政年份:2006
- 资助金额:
$ 38.38万 - 项目类别:
Structure-inhibition of amyloid oligomers and fibrils
淀粉样蛋白寡聚体和原纤维的结构抑制
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7866473 - 财政年份:2006
- 资助金额:
$ 38.38万 - 项目类别:
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