ROLE OF INFLAMMATION ON INDUCTION OF TAU PATHOLOGY IN THE BRAINS OF TRANSGENIC MI

炎症对转基因 MI 脑中 TAU 病理诱导的作用

基本信息

批准号：
8247739
负责人：
FRANK M LAFERLA
金额：
$ 25.6万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8247739
关键词：
Address Adopted Affect Age-Months Agreement Alzheimer&apos s Disease Amygdaloid structure Amyloid Anti-Inflammatory Agents Anti-inflammatory Antibodies Applications Grants Astrocytes Behavior Blood Vessels Brain Brain region Breeding Cerebral Amyloid Angiopathy Chronic Clinical Clinical Trials Cognition Cognitive deficits Collaborations Conditioned Culture Media Confounding Factors (Epidemiology)Data Deposition Development Double Effect Elements Encephalitis Epidemiologic Studies Event Exhibits Gene Expression Genetic Genotype Goals Harvest Hippocampus (Brain)Human Immune Immune system In Vitro Inflammation Inflammatory Inflammatory Response Interleukin-1 Knowledge Laboratories Lead Lesion Link Mediating Mediator of activation protein Microglia Molecular Mus Neurofibrillary Tangles Neuronal Plasticity Outcome Study Pathogenesis Pathologic Pathology Pathway interactions Patients Pattern Pharmaceutical Preparations Play Principal Investigator Protective Agents Regulatory Element Reporting Resources Role Senile Plaques Severities Signal Transduction Site Slice Staging Sum System Testing Therapeutic Thioflavin S Toxic effect Transgenes Transgenic Mice Transgenic Model Transgenic Organisms Up-Regulation Work aged apolipoprotein E-3 apolipoprotein E-4 brain pathway cytokine design embryo cell mutant neuropathology novel pre-clinical presenilin programs protein aggregate tau Proteins tau interaction tau phosphorylation tau-protein kinase transgenic model of alzheimer disease

项目摘要

Project 3: Role of Inflammation on Induction of Tau Pathology in the Brains of Transgenic Mice The Alzheimer disease (AD) brain is characterized by two types of protein aggregates, neurofibrillary tangles and amyloid plaques, which are found predominantly in the hippocampus, amygdala, and cortex. The buildup of Bamyloid (AB) and tau pathology is believed to directly cause or contribute to the progressive cognitive deficits. Because APP and/or presenilin mutant transgenic mice do not develop neurofibrillary pathology despite extensive plaque deposition, the introduction of multiple transgenes into the mouse germline is required to produce both hallmark lesions in mice. My lab recently derived a triple transgenic model of AD (3xTg-AD) in which both plaques and tangles develop in AD-relevant brain regions. The mice were derived by co-injecting human APPswe and tauP301L transgenes, both under the control of the Thyl.2 regulatory element, into single cell embryos harvested from PS1M146V homozygous knockin mice. The mice generated via this strategy are on the same genetic background (thereby avoiding an important confounding variable), breed efficiently (as easily as a single transgenic strain), and exist in both a hemizygous and homozygous genotype (allowing one to assess the effects of doubling gene expression on cognition in mice of the same genetic background). The 3xTg-AD mice represent a critical new resource for understanding the relationship between AB and tau interactions. Preliminary data from our laboratory show that AB can directly affect the tau pathology, as genetic or pharmacological approaches that modulate AB levels have a direct effect on tau pathology. In contrast, modulating tau levels through genetic or pharmacological means does not appear to significantly affect AB pathology. The sum of these studies indicates that AB lies upstream of tau in the pathogenic cascade. The primary focus of this grant application is to better elucidate the pathways by which AB modulates tau pathology in the 3xTg-AD mice. Although evidence from our laboratory indicates that AB likely affects tau pathology through several different mechanisms, one of the key pathways appears to involve microglial-mediated inflammation. Here we propose to elucidate the immune mediated mechanisms by which AB modulates tau pathology. Four specific aims are proposed: Aim 1 will determine the role that microglia play in the induction of the tau pathology. Aim 2 will investigate the role of inflammation in mice with advanced neuropathology and whether it exacerbates or ameliorates the pathology. Aim 3 proposes to use a genetic or pharmacologic approach to selectively increase IL1 levels in the brains of the 3xTg-AD mice to test the hypothesis that IL1 is a potent mediator that increases the severity of plaques and tangles. The last aim proposes to determine the effect that cerebral amyloid angiopathy has on inflammation, and focuses on crossing the 3xTg-AD mice to the ApoE3 and ApoE4 knockin mice.

项目 3：炎症对转基因小鼠大脑中 Tau 病理学诱导的作用阿尔茨海默病 (AD) 大脑的特点是有两种类型的蛋白质聚集体：神经原纤维缠结和淀粉样斑块，主要存在于海马体、杏仁核和皮质中。巴淀粉样蛋白的积累 (AB) 和 tau 蛋白病理学被认为直接导致或促成进行性认知缺陷。因为 APP 和/或早老素突变转基因小鼠尽管广泛的斑块沉积，需要将多个转基因引入小鼠种系在小鼠中产生两种标志性损伤。我的实验室最近在斑块和缠结均在与 AD 相关的大脑区域中形成。这些小鼠是通过共注射获得的将人类 APPswe 和 tauP301L 转基因（均在 Thyl.2 调控元件的控制下）导入单细胞从 PS1M146V 纯合敲入小鼠中收获的胚胎。通过该策略生成的小鼠位于相同的遗传背景（从而避免重要的混杂变量），高效繁殖（就像单一转基因菌株），并且存在半合子和纯合基因型（允许人们评估基因表达加倍对具有相同遗传背景的小鼠认知的影响）。 3xTg-AD 小鼠代表了理解 AB 和 tau 相互作用之间关系的重要新资源。初步的我们实验室的数据表明，AB 可以直接影响 tau 病理学，如遗传或药理学调节 AB 水平的方法对 tau 病理有直接影响。相反，调节 tau 水平通过遗传或药理学手段似乎不会显着影响 AB 病理学。总和这些研究表明 AB 位于致病级联中 tau 蛋白的上游。本次资助的主要重点该应用的目的是更好地阐明 AB 在 3xTg-AD 小鼠中调节 tau 病理学的途径。尽管我们实验室的证据表明 AB 可能通过几种不同的方式影响 tau 病理学机制中，关键途径之一似乎涉及小胶质细胞介导的炎症。在此我们建议阐明 AB 调节 tau 病理学的免疫介导机制。四个具体目标是建议：目标 1 将确定小胶质细胞在诱导 tau 病理学中所起的作用。目标2将研究炎症在患有晚期神经病理学的小鼠中的作用以及它是否加剧或改善病理学。目标 3 提出使用遗传或药理学方法选择性增加 IL1 3xTg-AD 小鼠大脑中的水平，以检验 IL1 是一种有效介质，可增加斑块和缠结的严重程度。最后一个目标是确定脑淀粉样血管病的影响研究人员针对炎症进行了研究，重点是将 3xTg-AD 小鼠与 ApoE3 和 ApoE4 敲入小鼠进行杂交。