文献检索，用中文搜 PubMed

Extracellular vesicles (EV), key players in cell-to-cell communication, may contribute to disease propagation in several neurodegenerative diseases, including Alzheimer's disease (AD), by favoring the dissemination of neurotoxic proteins within the brain. Interestingly, growing evidence supports the role of herpes simplex virus type 1 (HSV-1) infection in the pathogenesis of AD. Here, we investigated whether HSV-1 infection could promote the spread of phosphorylated tau (ptau) among neurons via EV. We analyzed the ptau species that were secreted via EV following HSV-1 infection in neuroblastoma cells and primary neurons, focusing particularly on T205, T181, and T217, the phosphorylation sites mainly associated with AD. Moreover, by overexpressing human tau tagged with GFP (htau), we found that recipient tau knockout (KO) neurons uptook EV that are loaded with HSV-1-induced phtau. Finally, we exploited an model of acute infection and assessed that cerebral HSV-1 infection promotes the release of ptau via EV in the brain of infected mice. Overall, our data suggest that, following HSV-1 infection, EV play a role in tau spreading within the brain, thus contributing to neurodegeneration.IMPORTANCEHerpes simplex virus type 1 (HSV-1) infection that reaches the brain has been repeatedly linked with the appearance of the pathognomonic markers of Alzheimer's disease (AD), including accumulation of amyloid beta and hyperphosphorylated tau proteins, and cognitive deficits. AD is a multifactorial neurodegenerative disease representing the most common form of dementia in the elderly, and no cure is currently available, thus prompting additional investigation on potential risk factors and pathological mechanisms. Here, we demonstrate that the virus exploits the extracellular vesicles (EV) to disseminate phosphorylated tau (ptau) among brain cells. Importantly, we provide evidence that the HSV-1-induced EV-bearing ptau can be undertaken by recipient neurons, thus likely contributing to misfolding and aggregation of native tau, as reported for other AD models. Hence, our data highlight a novel mechanism exploited by HSV-1 to propagate tau-related damage in the brain.

细胞外囊泡（EV）是细胞间通讯的关键参与者，它们可能通过促进脑内神经毒性蛋白的传播，导致几种神经退行性疾病（包括阿尔茨海默病（AD））的疾病进展。有趣的是，越来越多的证据支持单纯疱疹病毒 1 型（HSV-1）感染在 AD 发病机制中的作用。在这里，我们研究了 HSV-1 感染是否可以通过 EV 促进磷酸化 tau（ptau）在神经元中的传播。我们分析了神经母细胞瘤细胞和原代神经元中 HSV-1 感染后通过 EV 分泌的 ptau 物种，特别关注主要与 AD 相关的 T205、T181 和 T217 磷酸化位点。此外，通过过表达带有 GFP（htau）标记的人 tau，我们发现接受者 tau 敲除（KO）神经元摄取了含有 HSV-1 诱导的 phtau 的 EV。最后，我们利用急性感染模型，并评估了脑内 HSV-1 感染通过 EV 促进感染小鼠脑内 ptau 的释放。总的来说，我们的数据表明，在 HSV-1 感染后，EV 在脑内 tau 的传播中发挥作用，从而导致神经退行性变。

单纯疱疹病毒 1 型（HSV-1）感染到达大脑已被反复与阿尔茨海默病（AD）的标志性标志物的出现联系在一起，包括淀粉样β和过度磷酸化的 tau 蛋白的积累，以及认知缺陷。AD 是一种多因素神经退行性疾病，是老年人最常见的痴呆形式，目前尚无治愈方法，因此需要进一步研究潜在的危险因素和病理机制。在这里，我们证明病毒利用细胞外囊泡（EV）在脑细胞之间传播磷酸化 tau（ptau）。重要的是，我们提供了证据表明，HSV-1 诱导的携带 ptau 的 EV 可以被受者神经元摄取，从而可能导致与其他 AD 模型报道的天然 tau 的错误折叠和聚集。因此，我们的数据强调了 HSV-1 用于在大脑中传播 tau 相关损伤的新机制。