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

阿尔茨海默病(AD)与细胞外斑块中淀粉样β蛋白(ABETA)和细胞内神经原纤维缠结中过度磷酸化的tau蛋白积聚以及慢性神经炎有关。所有这些加在一起会导致进行性神经元丢失，最终导致认知能力下降和记忆力丧失。尽管阿尔茨海默病是世界上最常见的痴呆症形式，但目前还没有治愈甚至改善疾病的治疗方法。根据淀粉样级联假说，tau病理在AD患者abeta斑块形成的下游发展，但这两种病理之间的机制联系仍然难以捉摸。根据淀粉样蛋白级联假说，tau的播种和扩散可以由纤维淀粉样β蛋白诱导，这一机制被称为交叉播种。然而，减少患者的淀粉样斑块负担似乎并不能减缓疾病的进展，而且tau病理与临床症状的相关性要好得多。这提示另一条途径参与了AD的发生发展。过去几年的研究表明，在反应性小胶质细胞存在的情况下，tau病理的发展会加速，小胶质细胞是大脑自身免疫系统的关键参与者。相反，小胶质细胞的耗尽会导致tau在细胞间扩散的减少。有趣的是，小胶质细胞在阿尔茨海默病的发展过程中被长期激活，因为它们试图从大脑中清除阿贝塔。因此，我们假设激活的小胶质细胞在tau种子的形成和淀粉样β蛋白下游的扩散中起作用。为了研究这一潜在的机制，我们将首先确认激活的小胶质细胞对tau扩散的影响。其次，我们将分析激活或耗尽的小胶质细胞在不同的细胞培养和小鼠模型中对阿贝塔诱导的tau交叉种植的影响。第三，我们将研究NLRP3炎症体在小鼠的炎症体基因敲除后通过诱导tau交叉播种来控制小胶质细胞中促炎细胞因子的产生的作用。最后，我们将确定发生abeta病理的小鼠的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，我们的方法可以揭示AD的一个长期存在的问题，并有助于更好地了解疾病的发展。这最终可能导致针对大脑过度反应的免疫系统的新治疗策略。

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.