斯坦福大学医学院Tony Wyss-Coray小组近日取得一项新成果。经过不懈努力，他们提出了衰老促进了慢降解突触蛋白的小胶质细胞积累。2026年1月21日出版的《自然》发表了这项成果。

在这里，该课题组研究人员设计了生物正交工具，使他们能够标记新生的神经元蛋白质组，并研究其随着衰老的更新，其聚集倾向以及与小胶质细胞的相互作用。研究人员发现，在4个月大和24个月大的小鼠中，神经元蛋白的半衰期平均大约增加了一倍，个体蛋白的稳定性在大脑区域之间存在差异。

此外，该研究团队还描述了衰老的神经元“聚合体”，其中包含1726种蛋白质，其中近一半的蛋白质随着年龄的增长而退化。聚集组包括与疾病相关的众所周知的蛋白质和许多以前与神经变性无关的蛋白质。值得注意的是，该课题组研究人员证明了神经元蛋白在衰老的小胶质细胞中积累，54%的小胶质细胞也显示出随着年龄的增长降解和/或聚集减少。在这些蛋白中，突触蛋白是高度富集的，这表明从突触蛋白的转换和聚集受损到这些蛋白的处置，可能是通过突触的小胶质吞噬而发生的一连串事件。这些发现表明，随着年龄的增长，神经元蛋白质组的维持能力大幅下降，这可能导致与年龄相关的突触丧失和认知能力下降。

据介绍，全球每12个人中就有1人患有神经退行性疾病，而且仍然无法治愈。其发病机制的核心是神经元蛋白质维持能力的丧失和随着年龄增长而积累的蛋白质聚集体。

附：英文原文

Title: Ageing promotes microglial accumulation of slow-degrading synaptic proteins

Author: Guldner, Ian H., Wagner, Viktoria P., Moran-Losada, Patricia, Shi, Sophia M., Golub, Sophia W., Hevler, Johannes F., Chen, Kelly, Meese, Barbara T., Ghoochani, Ali, Pulido, Ernst, Oh, Hamilton Se-Hwee, Le Guen, Yann, Lu, Nannan, Wong, Pui Shuen, To, Ning-Sum, Garceau, Dylan, Guo, Zimin, Luo, Jian, Bertozzi, Carolyn R., Lundberg, Emma, Abu-Remaileh, Monther, Sasner, Michael, Keller, Andreas, Yang, Andrew C., Cheung, Tom H., Wyss-Coray, Tony

Issue&Volume: 2026-01-21

Abstract: Neurodegenerative diseases affect 1 in 12 people globally and remain incurable. Central to their pathogenesis is a loss of neuronal protein maintenance and the accumulation of protein aggregates with ageing1,2. Here we engineered bioorthogonal tools3 that enabled us to tag the nascent neuronal proteome and study its turnover with ageing, its propensity to aggregate and its interaction with microglia. We show that neuronal protein half-life approximately doubles on average between 4-month-old and 24-month-old mice, with the stability of individual proteins differing among brain regions. Furthermore, we describe the aged neuronal ‘aggregome’, which encompasses 1,726 proteins, nearly half of which show reduced degradation with age. The aggregome includes well-known proteins linked to diseases and numerous proteins previously not associated with neurodegeneration. Notably, we demonstrate that neuronal proteins accumulate in aged microglia, with 54% also displaying reduced degradation and/or aggregation with age. Among these proteins, synaptic proteins are highly enriched, which suggests that there is a cascade of events that emerge from impaired synaptic protein turnover and aggregation to the disposal of these proteins, possibly through microglial engulfment of synapses. These findings reveal the substantial loss of neuronal proteome maintenance with ageing, which could be causal for age-related synapse loss and cognitive decline.

DOI: 10.1038/s41586-025-09987-9

Source: https://www.nature.com/articles/s41586-025-09987-9