Cellular mechanisms facilitating the spreading of Tau pathology in Alzheimer's disease: uptake, release and synaptic cell-to-cell transmission of Tau nano-aggregates in neuronal networks

在阿尔茨海默病(AD)和其他痴呆症疾病中，异常的Tau蛋白聚集扩散到患者的大脑。因此，Tau的病理进展遵循一定的模式，并与神经退行性变的阶段相关。在阿尔茨海默病患者的大脑中，原本可以溶解的牛磺酸的长纤维聚集体聚集在神经纤维缠结(NFT)中。然而，Tau和其他蛋白质的小的可溶纳米聚集体最近被认为是各种神经退行性疾病的感染性和毒性物种，如阿尔茨海默病、帕金森病和Pron病。该项目的目的是研究可溶性Tau纳米聚集体是否以及如何触发神经元Tau的细胞内聚集并通过神经元网络传播。为了研究Tau聚集体的细胞摄取、释放和突触神经元向神经元传递的机制，我们将在定制的微流体设备中培养小鼠神经元，使我们能够生成最小的两个神经元网络。利用基于荧光的Tau聚集分析、高分辨率光学显微镜和不同的生物物理方法，我们将在单细胞水平上阐明可溶性Tau聚集在AD中的作用。我们的结果将启发神经退行性疾病中蛋白质聚集的细胞过程。

In Alzheimer’s disease (AD) and other dementia diseases, abnormal Tau protein aggregation spreads through-out the patient’s brain. Thereby, the progression of Tau pathology follows a certain pattern and correlates with the stage of neurodegeneration. In AD brains, long fibrillar aggregates of otherwise soluble Tau accumulate in neurofibrillar tangles (NFTs). However, small soluble nano-aggregates of Tau and other proteins are recently discussed as infective and toxic species in various neurodegenerative diseases such as AD, Parkinson’s and prion diseases. The aim of this project is to examine whether and how soluble Tau nano-aggregates trigger the intracellular aggregation of neuronal Tau and travel through neuronal networks. To study the mechanisms of cellular uptake, release and synaptic neuron-to-neuron transmission of Tau aggregates, mouse neurons will be cultured in custom-made microfluidic devices that enable us to generate minimal, two-neuron networks. Using fluorescence-based Tau aggregation assays, high-resolution light-microscopy and different biophysical methods we will elucidate the role of soluble Tau aggregates in AD on the single cell level. Our results will enlighten the cellular processes behind progressive protein aggregation in neurodegenerative diseases.