GFAP与阿尔茨海默病中星形胶质细胞活化的遗传密码

摘要(中文译文)

星形胶质细胞在控制中枢神经系统（CNS）稳态、突触、代谢和神经免疫通信中起着至关重要的作用。越来越多的证据表明，星形胶质细胞功能障碍在阿尔茨海默病（AD）的发病机制中起主导作用。反应性星形胶质增生以细胞肥大、转录重编程和胶质纤维酸性蛋白（GFAP）表达升高为特征，在淀粉样蛋白β积累、神经炎症和血脑屏障（BBB）破坏的早期即出现。转录、表观遗传和炎症信号传导，包括JAK/STAT3、NF-KB、MAPK和非编码RNA，控制着GFAP的表达，GFAP是一种结构性中间丝蛋白。高GFAP显示星形胶质细胞活化，以及部分神经元支持中断、谷氨酸失衡、氧化应激和类淋巴清除缺陷。因此，GFAP是脑脊液、血浆和唾液中一种有效的生物标志物，与淀粉样蛋白病理、认知障碍和AD相关。关于星形胶质细胞对GFAP反应的认识可用于提取有关AD机制的重要信息，并寻找识别诊断、预后和治疗的机会。

Abstract

Astrocytes play a crucial role in controlling homeostasis of the central nervous system (CNS), synapse, metabolism and neuroimmune communications. The growing body of evidence indicates that astrocyte dysfunction plays the leading role in the pathogenesis of Alzheimer's disease (AD). Reactive astrogliosis, characterised by cell hypertrophy, transcriptional reprogramming, and elevated glial fibrillary acidic protein (GFAP) expression, arises early in response to amyloid-β accumulation, neuroinflammation, and blood-brain barrier (BBB) disruption. Transcriptional, epigenetic and inflammatory signalling, including JAK/STAT3, NF-KB, MAPK and non-coding RNAs, control the expression of GFAP, which is a structural intermediate filament protein. High GFAP shows activation of astrocytes and a part of disrupted neuronal support, glutamate imbalance, oxidative distress and defective glymphatic clearance. Consequently, GFAP is an efficient biomarker in CSF, plasma, and saliva, which is associated with amyloid pathology, cognitive impairment, and AD. The knowledge of the astrocyte responses to GFAP can be used to extract significant information about AD mechanisms and find opportunities to identify diagnosis, prognosis and therapy.

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