AD重磅突破：Bassoon加剧Tau蛋白的病理性播散及其诱导的神经变性过程

中文摘要

Tau聚集是阿尔茨海默病和其他Tau蛋白病的一个明确的组织病理学特征。然而，tau蛋白病理播散的细胞机制仍不清楚。在这里，研究人员进行了一项无偏倚的定量蛋白质组学研究，以确定与tau种子特异性相互作用的蛋白质。他们鉴定了Bassoon（BSN），一种突触前支架蛋白，可作为tau种子的相互作用因子，而这种tau种子是从tau蛋白病小鼠模型、阿尔茨海默病和进行性核上性麻痹尸检样本中分离出来。他们的研究表明，BSN在小鼠和果蝇的tau蛋白病模型中都会加剧tau蛋白的播散和毒性，BSN的下调会减少tau蛋白的播散和整体疾病病理，逆转突触和行为损伤，并减轻脑萎缩。他们的发现Tau种子的播散可被一些相互作用蛋白，如BSN，所稳定。抑制tau蛋白种子相互作用是神经退行性tau蛋白病的潜在新治疗方法。

英文摘要

Tau aggregation is a defining histopathological feature of Alzheimer's disease and other tauopathies. However, the cellular mechanisms involved in tau propagation remain unclear. Here, we performed an unbiased quantitative proteomic study to identify proteins that specifically interact with this tau seed. We identified Bassoon (BSN), a presynaptic scaffolding protein, as an interactor of the tau seed isolated from a mouse model of tauopathy, and from Alzheimer's disease and progressive supranuclear palsy postmortem samples. We show that BSN exacerbates tau seeding and toxicity in both mouse and Drosophila models for tauopathy, and that BSN downregulation decreases tau spreading and overall disease pathology, rescuing synaptic and behavioral impairments and reducing brain atrophy. Our findings improve the understanding of how tau seeds can be stabilized by interactors such as BSN. Inhibiting tau-seed interactions is a potential new therapeutic approach for neurodegenerative tauopathies.