Role of microglia in amyloid beta-induced tau cross-seeding and spread

小胶质细胞在β淀粉样蛋白诱导的tau蛋白交叉播种和传播中的作用

• 批准号: 392521896
• 负责人: Dr. Christina Ising
• 金额: --
• 依托单位: Cluster of Excellence: Cellular Stress Responses in Aging-Associated Diseases
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/392521896?language=en
• 关键词: Role; microglia; amyloid; beta; induced

Alzheimer's disease (AD) is associated with accumulation of amyloid-beta (abeta) in extracellular plaques and hyperphosphorylated tau in intracellular neurofibrillary tangles as well as chronic neuroinflammation. All of this taken together leads to progressive neuronal loss, ultimately resulting in cognitive decline and memory loss. Even though AD is the most common form of dementia worldwide, no cure or even disease-modifying treatment exists.According to the amyloid cascade hypothesis, tau pathology develops downstream of abeta plaque formation in AD but the mechanistic link between these two pathologies remains elusive. In line with the amyloid cascade hypothesis, tau seeding and spreading can be induced by fibrillar amyloid-beta, a mechanism known as cross-seeding. However, reducing amyloid plaque burden in patients does not seem to slow disease progression and tau pathology correlates much better with clinical symptoms. This suggest the involvement of another pathway in the development of AD. Research over the past years showed that the development of tau pathology is accelerated in the presence of reactive microglia, an essential player of the brain's own immune system. Conversely, microglia depletion leads to reduced tau spread from cell to cell. Interestingly, microglia are chronically activated during the progression of AD as they attempt to clear abeta from the brain. Therefore, we hypothesize that activated microglia play a role in the development of tau seeding and spreading downstream of amyloid-beta. To investigate this potential mechanism, we will first confirm an effect of activated microglia on tau spread. Second, we will analyze the effects of activated or depleted microglia on abeta-induced tau cross-seeding in different cell culture and mouse models. Third, we will study the role of the NLRP3 inflammasome, which controls the generation of pro inflammatory cytokines in microglia, by inducing tau cross seeding after genetic knockout of the inflammasome in mice. Last, we will determine if the presence of microglia from mice, that develop abeta pathology, are sufficient to induce tau pathology in cell culture and mouse models.Taken together, our approach could shed light on a long standing question in AD and could help to better understand disease development. This could ultimately lead to new treatment strategies by targeting the brain's over-reacting immune system.

阿尔茨海默病（AD）与细胞外斑块中淀粉样蛋白- β (β)的积累和细胞内神经原纤维缠结中过度磷酸化的tau蛋白以及慢性神经炎症有关。所有这些加在一起会导致进行性神经元丧失，最终导致认知能力下降和记忆力丧失。尽管阿尔茨海默氏症是世界上最常见的痴呆症，但目前还没有治愈或改善疾病的治疗方法。根据淀粉样蛋白级联假说，AD中tau病理发生在β斑块形成的下游，但这两种病理之间的机制联系尚不清楚。与淀粉样蛋白级联假说一致，tau蛋白的播种和扩散可以由纤维状淀粉样蛋白- β诱导，这是一种被称为交叉播种的机制。然而，减少患者的淀粉样斑块负担似乎并不能减缓疾病进展，而且tau病理学与临床症状的相关性更好。这表明在阿尔茨海默病的发展中涉及另一途径。过去几年的研究表明，反应性小胶质细胞（大脑自身免疫系统的重要参与者）的存在加速了tau病理的发展。相反，小胶质细胞耗竭导致tau蛋白在细胞间传播减少。有趣的是，小胶质细胞在阿尔茨海默病的发展过程中被慢性激活，因为它们试图从大脑中清除β。因此，我们假设活化的小胶质细胞在tau种子的发育和淀粉样蛋白下游的扩散中发挥作用。为了研究这种潜在的机制，我们将首先确认激活的小胶质细胞对tau扩散的影响。其次，我们将在不同的细胞培养和小鼠模型中分析激活或耗尽小胶质细胞对β诱导的tau交叉播种的影响。第三，我们将通过基因敲除小鼠炎症小体后诱导tau交叉播种，研究NLRP3炎症小体在小胶质细胞中控制促炎细胞因子产生的作用。最后，我们将确定小鼠小胶质细胞的存在是否足以在细胞培养和小鼠模型中诱导tau病理。综上所述，我们的方法可以阐明阿尔茨海默病长期存在的问题，并有助于更好地了解疾病的发展。这可能最终导致针对大脑过度反应免疫系统的新治疗策略。