The Role of Inflammation and NGF Dysfunction in the Evolution of AlzheimerDisease Pathology in Down syndrome
炎症和 NGF 功能障碍在唐氏综合症阿尔茨海默病病理学演变中的作用
基本信息
- 批准号:10250064
- 负责人:
- 金额:$ 56.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-04-01 至 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:AdolescentAdultAffectAgeAlzheimer&aposs DiseaseAlzheimer&aposs disease pathologyAlzheimer&aposs disease riskAlzheimer’s disease biomarkerAmyloid beta-ProteinAppearanceAutopsyBiochemicalBiologicalBiological MarkersBody FluidsBrainCaliforniaCanadaCell Culture TechniquesCellsChromosome 21ClinicalCognitiveCognitive deficitsComplementDataDementiaDepositionDiagnosticDiseaseDisease ProgressionDown SyndromeElderlyEvolutionFunctional disorderGenesGenetic DiseasesGenetic ModelsGoalsHospitalsHumanHuman ChromosomesImpaired cognitionIn VitroIndividualInfantInflammationInflammatoryInvestigationLinkLiquid substanceLive BirthLongevityMeasuresMetabolic PathwayMetabolic dysfunctionMetabolismMolecularMolecular GeneticsNerve Growth FactorsNeurofibrillary TanglesNew YorkPathogenesisPathologyPathway interactionsPatientsPenetrancePeptidesPhasePlasmaPopulationProcessProteomicsQuantitative Reverse Transcriptase PCRRegulationRiskRoleSamplingSenile PlaquesSignal TransductionSpainStudy modelsSystemTestingTissuesTranscriptTrisomyUniversitiesWestern Blottingabeta accumulationasymptomatic Alzheimer’s diseasebasal forebrainbasebiomarker discoverycholinergicclinically relevantcohortdevelopmental geneticsearly detection biomarkersextracellularfetalhigh riskinflammatory markermultidisciplinaryneonateneuroinflammationnew therapeutic targetnovelpotential biomarkerpre-clinicaltau Proteinstau-1tool
项目摘要
PROJECT SUMMARY/ABSTRACT
Individuals at risk of Alzheimer’s disease (AD) undergo a long, asymptomatic phase of disease
progression that is characterized by the gradual accumulation of pathology in the absence of apparent
cognitive deficit. Down syndrome (DS) patients represent a population at high risk of AD with complete
penetrance of AD pathology in the majority of DS subjects, making DS an outstanding natural genetic model
for the study of neuropathological mechanisms of AD and for identifying potential AD biomarkers. Given the
current limitations in reliable early diagnostic tools, the discovery of biomarkers signalling the evolution of
Alzheimer’s disease pathology in individuals at risk, including those with DS, is of utmost clinical relevance.
The overall goal of the current proposal is to investigate novel, uncharacterized biomarkers at
the earliest preclinical stages of AD in DS. To achieve this goal, a collaborative effort will integrate data from
post-mortem brain studies, primary human cell cultures studies, and biological fluids (plasma and CSF) studies
in a large well-characterized cohort of DS and matched control subjects.
The central hypothesis of the proposal is that the early accumulation of intracellular amyloid beta
peptide (Aβ) in DS brains will induce CNS inflammation accompanied by NGF metabolic dysfunction
prior to extracellular amyloid plaque deposition. Furthermore, the CNS compromise of NGF
metabolism should be detected in DS body fluids at ‘incipient’ stages of the AD pathology, before the
presentation of overt dementia.
To test the stated hypothesis, three Specific Aims will be accomplished: Aim 1: To explore the
occurrence of a CNS pro-inflammatory process and NGF dysfunction throughout the lifespan in DS. Using
post-mortem DS brains at different ages, the appearance of inflammation and NGF dysfunction in DS will be
investigated to temporally reconstruct the evolution of AD pathogenesis. Aim 2: To investigate molecular
mechanisms that link early AD pathology in DS with neuroinflammation and NGF metabolic dysfunction using
fetal human primary cortical cultures. These studies will complement Aims 1 and 3 and will elucidate molecular
pathways underlying early AD pathogenesis. Aim 3: To analyze the expression of Aβ, tau, NGF-related and
inflammatory markers in matched plasma and CSF samples from DS subjects across the lifespan. These
studies will test whether markers investigated in Aims- 1 and -2 are reflected in matched plasma and CSF
samples from DS versus control subjects.
This multi-PI multidisciplinary proposal will reveal fundamental molecular pathobiological mechanisms
for AD in DS, it will identify biomarkers, and it will assist in the prediction of the onset and trajectory of
dementia. In addition, the planned studies will likely lead to the identification of novel therapeutic targets in both
DS individuals and sporadic AD populations.
项目总结/摘要
有患阿尔茨海默病风险的个体经历了一个漫长的、无症状的疾病阶段
进展,其特征是在没有明显的
认知缺陷唐氏综合征(DS)患者代表AD高风险人群,
在大多数DS受试者中发现AD病理学的异常,使DS成为一种杰出的自然遗传模型
用于研究AD的神经病理学机制和用于鉴定潜在的AD生物标志物。鉴于
目前可靠的早期诊断工具的局限性,生物标志物的发现,
阿尔茨海默病的病理学在个人的风险,包括那些与DS,是最大的临床相关性。
当前提案的总体目标是研究新的,未表征的生物标志物,
DS中AD的最早临床前阶段。为了实现这一目标,将通过协作努力整合来自
死后大脑研究、原代人类细胞培养研究和生物液体(血浆和CSF)研究
在DS和匹配对照受试者的大型充分表征队列中。
该提案的中心假设是,细胞内淀粉样β蛋白的早期积累
DS脑内Aβ肽可诱导中枢神经系统炎症反应,并伴有神经生长因子代谢障碍
在细胞外淀粉样斑块沉积之前。此外,神经生长因子的中枢神经系统损害
应在AD病理学的“初期”阶段,在
表现出明显的痴呆
为了检验所述假设,将实现三个具体目标:目标1:探索
在DS的整个生命周期中发生CNS促炎过程和NGF功能障碍。使用
在不同年龄的死后DS脑中,DS中炎症和NGF功能障碍的出现将是
研究以在时间上重建AD发病机制的演变。目的2:研究分子生物学
将DS的早期AD病理学与神经炎症和NGF代谢功能障碍联系起来的机制,
人胎原代皮层培养物。这些研究将补充目标1和目标3,并将阐明分子生物学的
早期AD发病机制的潜在途径。目的3:分析Aβ、tau蛋白、神经生长因子相关蛋白及神经胶质瘤的表达,
在整个生命周期内,DS受试者的匹配血浆和CSF样本中的炎症标志物。这些
研究将测试目标-1和2中研究的标志物是否反映在匹配的血浆和CSF中
DS与对照受试者的样本。
这个多PI多学科的建议将揭示基本的分子病理生物学机制
对于DS中的AD,它将识别生物标志物,并将有助于预测
痴呆此外,计划中的研究可能会导致在这两种疾病中发现新的治疗靶点。
DS个体和散发性AD人群。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Nerve Growth Factor Compromise in Down Syndrome.
- DOI:10.3389/fnagi.2021.719507
- 发表时间:2021
- 期刊:
- 影响因子:4.8
- 作者:Do Carmo S;Kannel B;Cuello AC
- 通讯作者:Cuello AC
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{{ truncateString('JORGE A BUSCIGLIO', 18)}}的其他基金
2nd International Conference of the Trisomy 21 Research Society
21三体研究会第二届国际会议
- 批准号:
9261363 - 财政年份:2016
- 资助金额:
$ 56.37万 - 项目类别:
Combinational pharmacotherapies for neuronal abnormalities in Down syndrome
唐氏综合症神经元异常的联合药物疗法
- 批准号:
8990998 - 财政年份:2015
- 资助金额:
$ 56.37万 - 项目类别:
iPSC from British and Danish dementias: new discovery tools for brain amyloidoses
来自英国和丹麦痴呆症的 iPSC:大脑淀粉样变性的新发现工具
- 批准号:
8652006 - 财政年份:2013
- 资助金额:
$ 56.37万 - 项目类别:
iPSC from British and Danish dementias: new discovery tools for brain amyloidoses
来自英国和丹麦痴呆症的 iPSC:大脑淀粉样变性的新发现工具
- 批准号:
8741917 - 财政年份:2013
- 资助金额:
$ 56.37万 - 项目类别:
ASTROCYTE-RELATED MOLECULAR MECHANISMS UNDERLYING ALTERED NEURONAL PLASTICITY IN
星形胶质细胞相关的神经元可塑性改变的分子机制
- 批准号:
8440519 - 财政年份:2000
- 资助金额:
$ 56.37万 - 项目类别:
ROLE OF ETS-2 AND SOD-1 IN DOWN SYNDROME NEUROPATHOLOGY
ETS-2 和 SOD-1 在唐氏综合症神经病理学中的作用
- 批准号:
6637056 - 财政年份:2000
- 资助金额:
$ 56.37万 - 项目类别:
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