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蛋白-β（abeta）的积累和细胞内神经元缠结中过度磷酸化的tau蛋白以及慢性神经炎症相关。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丧失。尽管AD是全世界最常见的痴呆形式，但没有治愈或甚至疾病修饰治疗存在。根据淀粉样蛋白级联假说，tau病理在AD中的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。与淀粉样蛋白级联假说一致，tau接种和扩散可以由纤维状淀粉样蛋白β诱导，这是一种称为交叉接种的机制。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，tau病理学与临床症状的相关性要好得多。这表明在AD的发展中涉及另一种途径。过去几年的研究表明，tau病理学的发展在反应性小胶质细胞的存在下加速，小胶质细胞是大脑自身免疫系统的重要参与者。相反，小胶质细胞耗竭导致tau从细胞到细胞的扩散减少。有趣的是，小胶质细胞在AD的进展过程中被长期激活，因为它们试图从大脑中清除abeta。因此，我们假设活化的小胶质细胞在tau蛋白播种和淀粉样蛋白-β下游扩散的发展中发挥作用。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，我们将分析激活或耗尽的小胶质细胞对不同细胞培养物和小鼠模型中abeta诱导的tau交叉接种的影响。第三，我们将研究NLRP 3炎性体的作用，其控制小胶质细胞中促炎细胞因子的产生，通过在小鼠中遗传敲除炎性体后诱导tau交叉接种。最后，我们将确定来自小鼠的小胶质细胞的存在，发展abeta病理，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AD中一个长期存在的问题，并有助于更好地了解疾病的发展。这可能最终导致新的治疗策略，针对大脑的过度反应的免疫系统。

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.