CAA, Tau and Neurodegeneration

CAA、Tau 蛋白和神经退行性变

• 批准号: 9982573
• 负责人: Cristian Lasagna-Reeves
• 金额: $ 4.72万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/9982573
• 关键词: Ablation; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid deposition; Amyloidosis; Animal Model; Attention; Behavioral; Biochemical; Blood Vessels; Brain Pathology; Cells; Cerebral Amyloid Angiopathy; Cerebral hemisphere hemorrhage; Cerebrum; Dementia; Deposition; Development; Disease; Exhibits; Functional disorder; Genetic; Goals; Human; Immune; Immune response; Impaired cognition; Inflammation; Inflammatory Response; Knockout Mice; Lead; Leptomeninges; Link; Modeling; Molecular; Mus; Mutation; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Pathogenesis; Pathologic; Pathology; Patients; Pericytes; Phenotype; Play; Process; Proteins; Research; Role; Study models; Synapses; TREM2 gene; Tamoxifen; Testing; Toxic effect; Transgenic Mice; Treatment Efficacy; Variant; Vascular Dementia; Work; abeta deposition; amyloid peptide; cerebrovascular; endothelial dysfunction; extracellular; genome wide association study; glial activation; gray matter; high risk; hyperphosphorylated tau; in vivo; in vivo Model; insight; mouse model; mutant; neurofibrillary tangle formation; neuroinflammation; neuron loss; neurotoxicity; new therapeutic target; overexpression; spatiotemporal; tau Proteins; tau aggregation; tau mutation; tau phosphorylation; vascular contributions; white matter

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.

总结 阿尔茨海默病（AD）是最常见的痴呆形式，其特征在于细胞外沉积的 实质和血管β-淀粉样蛋白（A β），tau的细胞内积累作为神经元缠结（NFT）， 神经元细胞损失和显著炎症1，2.在过去的几十年里，研究的一个主要焦点是 对实质性Ablation、NFT和神经退行性变之间联系的理解， 血管病理对NFT和神经变性的作用仍在研究中。脑淀粉样 血管病（CAA）的典型特征是脑血管沉积的ARF，并有密切的分子关系， AD.不幸的是，目前还没有明确的分子和细胞机制和目标， CAA对神经退行性变和痴呆的作用。因此，本项目的主要目标 建议是剖析CAA导致神经炎症，异常 tau积累和神经变性。CAA与主动免疫反应有关， 过度磷酸化tau蛋白的血管周围沉积;然而，这三种病理实体从未被联系起来 与认知能力下降相关的时空背景。因此，我们建议确定一种疾病- 由促炎反应催化的相关形式的tau在行为缺陷中起主要作用， 在与CAA相关的痴呆中观察到的突触毒性，使用一种成熟的遗传小鼠模型， CAA（Tg-FDD）12.我们还将确定髓样细胞表达的触发受体2（TREM 2）是否在 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蛋白是否对CAA和随后的神经毒性起作用来确定tau蛋白的潜在作用。 在我们的遗传小鼠模型中，功能性内源性tau蛋白的消除抑制了行为缺陷和毒性 对于CAA。拟议的研究将为理解CAA在以下方面的作用提供一个平台 神经变性从这些研究中获得的信息可能有助于制定有效的 治疗不仅用于CAA和AD，而且用于许多特征在于 淀粉样肽的血管积聚。