Wang Yan-Jiang, Pollard Anthony, Zhong Jin-Hua, Dong Xiao-Yan, Wu Xiao-Bing, Zhou Hua-Dong, Zhou Xin-Fu
Department of Human Physiology and Centre for Neuroscience, Flinders University, SA, Australia.
Neurobiol Aging. 2009 Mar;30(3):364-76. doi: 10.1016/j.neurobiolaging.2007.06.013. Epub 2007 Aug 7.
Anti-beta-amyloid (Abeta) immunotherapy has been well documented to effectively elicit amyloid plaque clearance and slow cognitive decline in experimental and clinical studies. However, anti-Abeta immunotherapy was associated with detrimental effects of brain inflammation and microhemorrhage, presumably induced by T-cell-mediated and/or Fc-mediated inflammatory responses. In the present study, a single chain antibody (scFv) against Abeta could effectively inhibit the aggregation of Abeta and promote the disaggregation of preformed Abeta fibrils. The recombined adeno-associated virus vectors carrying the scFv gene were produced to delivery the scFv gene. Hippocampus delivery of the scFv gene was effective in reducing the amyloid plaque in the hippocampus of an Alzheimer's disease (AD) mouse model. Further studies demonstrated that intramuscular delivery of the scFv gene was as effective as intracranial delivery in reducing the total Abeta level in the brain with a concomitant elevated Abeta level in serum. No enhanced microglial activation, discernable T lymphocyte infiltration, and increased microhemorrhage were found after intracranial and intramuscular delivery of the scFv gene. Our results suggest that intramuscular delivery of the scFv gene would be a novel peripheral noninflammatory immunological modality targeting Abeta clearance and be promising in future drug development for the prevention and treatment of AD.
抗β淀粉样蛋白（Aβ）免疫疗法在实验和临床研究中已被充分证明能有效促使淀粉样斑块清除并减缓认知衰退。然而，抗Aβ免疫疗法与脑炎症和微出血的有害影响相关，推测是由T细胞介导和/或Fc介导的炎症反应所诱导。在本研究中，一种针对Aβ的单链抗体（scFv）能有效抑制Aβ的聚集并促进预先形成的Aβ纤维的解聚。构建了携带scFv基因的重组腺相关病毒载体以递送scFv基因。将scFv基因递送至海马体可有效减少阿尔茨海默病（AD）小鼠模型海马体中的淀粉样斑块。进一步研究表明，肌肉注射scFv基因在降低脑内总Aβ水平方面与颅内注射效果相当，同时血清中Aβ水平升高。在颅内和肌肉注射scFv基因后，未发现小胶质细胞激活增强、可辨别的T淋巴细胞浸润以及微出血增加。我们的结果表明，肌肉注射scFv基因将是一种针对Aβ清除的新型外周非炎性免疫方式，在未来AD预防和治疗的药物开发中具有前景。
