CAA, Tau and Neurodegeneration
CAA、Tau 蛋白和神经退行性变
基本信息
- 批准号:9982573
- 负责人:
- 金额:$ 4.72万
- 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:2018-08-15 至 2023-04-30
- 项目状态:已结题
- 来源:
- 关键词:AblationAffectAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease riskAmyloidAmyloid beta-ProteinAmyloid beta-Protein PrecursorAmyloid depositionAmyloidosisAnimal ModelAttentionBehavioralBiochemicalBlood VesselsBrain PathologyCellsCerebral Amyloid AngiopathyCerebral hemisphere hemorrhageCerebrumDementiaDepositionDevelopmentDiseaseExhibitsFunctional disorderGeneticGoalsHumanImmuneImmune responseImpaired cognitionInflammationInflammatory ResponseKnockout MiceLeadLeptomeningesLinkModelingMolecularMusMutationNerve DegenerationNeuraxisNeurodegenerative DisordersNeurofibrillary TanglesNeuronsPathogenesisPathologicPathologyPatientsPericytesPhenotypePlayProcessProteinsResearchRoleStudy modelsSynapsesTREM2 geneTamoxifenTestingToxic effectTransgenic MiceTreatment EfficacyVariantVascular DementiaWorkabeta depositionamyloid peptidecerebrovascularendothelial dysfunctionextracellulargenome wide association studyglial activationgray matterhigh riskhyperphosphorylated tauin vivoin vivo Modelinsightmouse modelmutantneurofibrillary tangle formationneuroinflammationneuron lossneurotoxicitynew therapeutic targetoverexpressionspatiotemporaltau Proteinstau aggregationtau mutationtau phosphorylationvascular contributionswhite matter
项目摘要
SUMMARY
Alzheimer disease (AD), the most common form of dementia, is characterized by the extracellular deposition of
parenchymal and vascular ß-amyloid (Aß), intracellular accumulation of tau as neurofibrillary tangles (NFTs),
neuronal cell loss, and significant inflammation1,2. During the past decades, a major focus of research has been
the understanding of the connection between parenchymal Aß, NFT, and neurodegeneration, with the
contribution of vascular pathology to NFT and neurodegeneration remaining under studied. Cerebral amyloid
angiopathy (CAA) is typified by the cerebrovascular deposition of Aß and has a close molecular relationship with
AD. Unfortunately, there is no clear understanding of the molecular and cellular mechanisms and targets that
underlie the contribution of CAA to neurodegeneration and dementia. Therefore, the main goal of this
proposal is to dissect the mechanism(s) by which CAA leads to neuroinflammation, abnormal
tau accumulation, and neurodegeneration. CAA has been associated to an active immune response and
perivascular deposition of hyperphosphorylated tau; yet these three pathological entities have never been linked
in a spatio-temporal context in relation to cognitive decline. Hence, we propose to determine if a disease-
associated form of tau, catalyzed by a pro-inflammatory response, plays a major role on behavioral deficit and
the synaptotoxicity observed in dementias associated to CAA, using a well-established genetic mouse model for
CAA (Tg-FDD)12. We will also determine if the triggering receptor expressed on myeloid cells 2 (TREM2) plays
a preponderant role in vascular amyloid deposition and vascular integrity in vivo during CAA progression.
Furthermore, we will identify the potential role of tau on CAA and subsequent neurotoxicity by determining if
the ablation of functional endogenous tau suppresses behavioral deficit and toxicity in our genetic mouse model
for CAA. The proposed studies will provide a platform for the understanding of the role of CAA in
neurodegeneration. Information gained from these studies might lead to the development of effective
therapeutics not only for CAA and AD, but also for a number of neurodegenerative diseases characterized by the
vascular accumulation of amyloid peptides.
摘要
阿尔茨海默病(AD)是痴呆症最常见的形式,其特征是细胞外沉积
实质和血管β-淀粉样蛋白(A?),tau在细胞内积聚为神经原纤维缠结(NFT),
神经细胞丢失和明显的炎症1,2。在过去的几十年里,研究的一个主要焦点是
对脑实质Aü、NFT和神经退行性变之间的联系的理解
血管病理对NFT和神经退行性变的作用仍在研究中。脑淀粉样蛋白
血管病(CAA)是以脑血管沉积为代表的疾病,与
广告。不幸的是,目前还没有明确的分子和细胞机制和靶点
CAA对神经退行性变和痴呆症的作用。因此,这一行动的主要目标是
建议解剖(S)CAA导致神经炎症、异常的机制
Tau蓄积和神经退行性变。CAA被认为与主动免疫反应和
过度磷酸化的tau蛋白在血管周围的沉积;然而这三种病理实体从未联系在一起
在与认知衰退有关的时空环境中。因此,我们建议确定一种疾病-
相关形式的tau在促炎反应的催化下,在行为缺陷和
在与CAA相关的痴呆中观察到的突触毒性,使用已建立的遗传小鼠模型
CAA(TG-FDD)12。我们还将确定髓样细胞上表达的触发受体2(TREM2)是否发挥作用
在CAA进展过程中,在体内血管淀粉样蛋白沉积和血管完整性中起主要作用。
此外,我们将通过确定tau在CAA和随后的神经毒性中的潜在作用来确定
去除功能性内源性tau抑制我们的遗传小鼠模型中的行为缺陷和毒性
对CAA来说。拟议的研究将提供一个平台,以了解CAA在
神经退行性变。从这些研究中获得的信息可能会导致开发有效的
不仅治疗CAA和AD,而且还治疗一些神经退行性疾病,特征是
淀粉样多肽的血管堆积。
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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Cristian Lasagna-Reeves其他文献
Cristian Lasagna-Reeves的其他文献
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{{ truncateString('Cristian Lasagna-Reeves', 18)}}的其他基金
Identify and study the roles of key genes and proteins in subpopulations of Alzheimer's disease patients with uncoupled neurofibrillary tangles
识别和研究关键基因和蛋白质在具有解偶联神经原纤维缠结的阿尔茨海默病患者亚群中的作用
- 批准号:
10525012 - 财政年份:2022
- 资助金额:
$ 4.72万 - 项目类别:
Tau-seed protein interactome and its role in neurodegenerative tauopathies
Tau 种子蛋白相互作用组及其在神经退行性 tau 病中的作用
- 批准号:
10456475 - 财政年份:2021
- 资助金额:
$ 4.72万 - 项目类别:
Tau-seed protein interactome and its role in neurodegenerative tauopathies
Tau 种子蛋白相互作用组及其在神经退行性 tau 病中的作用
- 批准号:
10407715 - 财政年份:2021
- 资助金额:
$ 4.72万 - 项目类别:
Tau-seed protein interactome and its role in neurodegenerative tauopathies
Tau 种子蛋白相互作用组及其在神经退行性 tau 病中的作用
- 批准号:
10480212 - 财政年份:2020
- 资助金额:
$ 4.72万 - 项目类别:
Tau-seed protein interactome and its role in neurodegenerative tauopathies
Tau 种子蛋白相互作用组及其在神经退行性 tau 病中的作用
- 批准号:
10470271 - 财政年份:2020
- 资助金额:
$ 4.72万 - 项目类别:
Tau-seed protein interactome and its role in neurodegenerative tauopathies
Tau 种子蛋白相互作用组及其在神经退行性 tau 病中的作用
- 批准号:
10683165 - 财政年份:2020
- 资助金额:
$ 4.72万 - 项目类别:
Tau-seed protein interactome and its role in neurodegenerative tauopathies
Tau 种子蛋白相互作用组及其在神经退行性 tau 病中的作用
- 批准号:
10268217 - 财政年份:2020
- 资助金额:
$ 4.72万 - 项目类别:
Tau-seed protein interactome and its role in neurodegenerative tauopathies
Tau 种子蛋白相互作用组及其在神经退行性 tau 病中的作用
- 批准号:
10093443 - 财政年份:2020
- 资助金额:
$ 4.72万 - 项目类别:
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