Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 5 Cutcombe Road, London SE5 9RX, UK.
UK Dementia Research Institute, UCL Institute of Neurology, University College London, London, UK.
Sci Adv. 2024 Mar 22;10(12):eadk9884. doi: 10.1126/sciadv.adk9884. Epub 2024 Mar 20.
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.
分子伴侣通过防止蛋白质错误折叠和聚集（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）在神经退行性疾病中具有保护作用。此外，AD 的特征还包括星形胶质细胞反应性增加。伴侣蛋白 HSPB1 已被提议作为反应性星形胶质细胞的标志物；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，我们确定 HSPB1 从星形胶质细胞分泌以发挥非细胞自主的保护功能。我们表明，在人类 AD 大脑中，HSPB1 水平在聚集在淀粉样斑块周围的星形胶质细胞以及相邻的细胞外空间中增加。此外，在模拟炎症反应性反应的条件下，星形胶质细胞增加 HSPB1 的分泌。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中炎症反应的减弱和病理性 tau 包涵体的减少。我们的发现强调了一种在疾病条件下的保护机制，包括通常被认为是细胞内的伴侣蛋白的分泌。
