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：
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
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：
https://reporter.nih.gov/project-details/9982573
关键词：
Ablation Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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

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.

概括阿尔茨海默氏病（AD）是痴呆的最常见形式，其特征是细胞外沉积副群和血管 - 淀粉样蛋白（Aß），Tau作为神经原纤维缠结（NFTS）的细胞内积累神经元细胞丧失和明显的炎症1,2。在过去的几十年中，研究的重点是对实质Aß，NFT和神经变性之间的联系的理解，血管病理对NFT和神经退行性的贡献。脑淀粉样蛋白血管病（CAA）的特征是Aß的脑血管沉积，与分子关系紧密广告。不幸的是，对分子和细胞机制和靶标没有明确的了解 CAA对神经变性和痴呆症的贡献是基础。因此，主要目标建议是剖析CAA导致神经炎症的机制，异常 tau加速度和神经变性。 CAA与主动免疫响应有关，并且热磷酸化tau的血管周期沉积；然而，这三个病理实体从未链接在与认知能力下降有关的时空环境中。因此，我们建议确定疾病是否 tau的相关形式，由促炎反应催化，在行为不足和在与CAA相关的痴呆症中观察到的突触毒性，使用公认 CAA（TG-FDD）12。我们还将确定在髓样细胞2（Trem2）上表达的触发受体是否表达在CAA进展过程中，在体内的血管淀粉样沉积和血管完整性中起主要作用。此外，我们将通过确定是否是否确定tau在CAA和随后的神经毒性上的潜在作用。功能性内源性TAU的消融抑制了我们的遗传小鼠模型中的行为不足和毒性对于CAA。拟议的研究将为理解CAA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导致有效的发展不仅用于CAA和AD的治疗，还针对许多以该疾病为特征淀粉样肽的血管积累。