Molecular chaperones are protective in neurodegenerative diseases by preventing protein misfolding and aggregation, such as extracellular amyloid plaques and intracellular tau neurofibrillary tangles in Alzheimer’s disease (AD). In addition, AD is characterized by an increase in astrocyte reactivity. The chaperone HSPB1 has been proposed as a marker for reactive astrocytes; however, its astrocytic functions in neurodegeneration remain to be elucidated. Here, we identify that HSPB1 is secreted from astrocytes to exert non–cell-autonomous protective functions. We show that in human AD brain, HSPB1 levels increase in astrocytes that cluster around amyloid plaques, as well as in the adjacent extracellular space. Moreover, in conditions that mimic an inflammatory reactive response, astrocytes increase HSPB1 secretion. Concomitantly, astrocytes and neurons can uptake astrocyte-secreted HSPB1, which is accompanied by an attenuation of the inflammatory response in reactive astrocytes and reduced pathological tau inclusions. Our findings highlight a protective mechanism in disease conditions that encompasses the secretion of a chaperone typically regarded as intracellular.

中文翻译：

---

反应性星形胶质细胞分泌伴侣 HSPB1 介导神经保护

分子伴侣通过防止蛋白质错误折叠和聚集，例如阿尔茨海默病 (AD) 中的细胞外淀粉样斑块和细胞内 tau 神经原纤维缠结，对神经退行性疾病起到保护作用。此外，AD的特征是星形胶质细胞反应性增加。伴侣 HSPB1 已被提议作为反应性星形胶质细胞的标记物；然而，其在神经退行性变中的星形胶质细胞功能仍有待阐明。在这里，我们发现 HSPB1 由星形胶质细胞分泌，发挥非细胞自主保护功能。我们发现，在人类 AD 大脑中，聚集在淀粉样斑块周围以及邻近细胞外空间的星形胶质细胞中 HSPB1 水平增加。此外，在模拟炎症反应反应的情况下，星形胶质细胞会增加 HSPB1 的分泌。与此同时，星形胶质细胞和神经元可以摄取星形胶质细胞分泌的 HSPB1，这伴随着反应性星形胶质细胞炎症反应的减弱和病理性 tau 包涵体的减少。我们的研究结果强调了疾病条件下的保护机制，其中包括通常被视为细胞内的伴侣的分泌。