星形胶质细胞控制健康人群和病患大脑的许多功能,包括控制再生反应。阿尔茨海默氏病的患者淀粉样蛋白斑沉积,神经元功能退化,同时星形胶质细胞变得异常活跃。到现在为止,许多研究人员认为,星形胶质细胞的过度活动发挥负调控作用,促进这种破坏性疾病阿尔茨海默氏症的进展。
在这项新研究中,美国和瑞典研究小组利用中,他们抑制阿尔茨海默氏症转基因老鼠模型中过度活跃的星形胶质细胞,结果发现与正常小鼠相比,这些小鼠的淀粉样蛋白沉积增多。
Milos Pekny教授说:现在,研究人员需要了解过度活跃的星形胶质细胞在阿尔茨海默氏症疾病进展中的机制。在分子水平上了解这个过程应该能帮助设计以星形胶质细胞为靶标的治疗策略。
Jin-Moo Lee教授表示:阿尔茨海默氏病患者大脑中星形胶质细胞的过度活跃与小胶质细胞的活化紧密相连,小胶质细胞是大脑的自身免疫细胞。这意味着,这两种细胞的沟通共同调解疾病发展。
这两个国际神经科学家合作团队正在进一步研究以了解星形胶质细胞的分子机制,希望能防止阿尔茨海默氏症中淀粉样蛋白斑块的沉积。(生物谷:Bioon.com)
doi:10.1096/fj.12-208660
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Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice
Andrew W. Kraft*, Xiaoyan Hu*, Hyejin Yoon*, Ping Yan*, Qingli Xiao*, Yan Wang*, et al.
The accumulation of aggregated amyloid-β (Aβ) in amyloid plaques is a neuropathological hallmark of Alzheimer's disease (AD). Reactive astrocytes are intimately associated with amyloid plaques; however, their role in AD pathogenesis is unclear. We deleted the genes encoding two intermediate filament proteins required for astrocyte activation—glial fibrillary acid protein (Gfap) and vimentin (Vim)—in transgenic mice expressing mutant human amyloid precursor protein and presenilin-1 (APP/PS1). The gene deletions increased amyloid plaque load: APP/PS1 Gfap?/?Vim?/? mice had twice the plaque load of APP/PS1 Gfap+/+Vim+/+ mice at 8 and 12 mo of age. APP expression and soluble and interstitial fluid Aβ levels were unchanged, suggesting that the deletions had no effect on APP processing or Aβ generation. Astrocyte morphology was markedly altered by the deletions: wild-type astrocytes had hypertrophied processes that surrounded and infiltrated plaques, whereas Gfap?/?Vim?/? astrocytes had little process hypertrophy and lacked contact with adjacent plaques. Moreover, Gfap and Vim gene deletion resulted in a marked increase in dystrophic neurites (2- to 3-fold higher than APP/PS1 Gfap+/+Vim+/+ mice), even after normalization for amyloid load. These results suggest that astrocyte activation limits plaque growth and attenuates plaque-related dystrophic neurites. These activities may require intimate contact between astrocyte and plaque.—Kraft, A. W., Hu, X., Yoon, H., Yan, P., Xiao, Q., Wang, Y., Gil, S. C., Brown, J., Wilhelmsson, U., Restivo, J. L., Cirrito, J. R., Holtzman, D. M., Kim, J., Pekny, M., Lee, J.-M. Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice.