Intramuscular delivery of a single chain antibody gene prevents brain Aβ deposition and cognitive impairment in a mouse model of Alzheimer’s disease
Intramuscular delivery of a single chain antibody gene prevents brain Aβ deposition and cognitive impairment in a mouse model of Alzheimer’s disease
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DOI：
10.1016/j.bbi.2010.05.010
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发表时间：
2010-11
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影响因子：
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通讯作者：
Yanjiang Wang;C. Gao;Miao Yang;Xiao-hong Liu;Ying Sun;A. Pollard;Xiaoyan Dong;Xiao-bing Wu;Jin‐hua Zhong;Huadong Zhou;Xin-Fu Zhou
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作者：
Yanjiang Wang;C. Gao;Miao Yang;Xiao-hong Liu;Ying Sun;A. Pollard;Xiaoyan Dong;Xiao-bing Wu;Jin‐hua Zhong;Huadong Zhou;Xin-Fu Zhou
抗β-淀粉样蛋白（A β）免疫疗法可有效清除脑A β，但已显示与有害作用相关。我们已经证明，腺相关病毒（AAV）介导的抗A β单链抗体（scFv）基因的递送在老年APPSwe/PS1dE9转基因小鼠中可有效清除脑A β，而不会引发任何炎症副作用。在本研究中，我们测试了肌肉注射scFv基因预防脑A β沉积的有效性和安全性。将scFv基因肌肉注射到3月龄的APPSwe/PS1dE9转基因小鼠中，然后在脑中沉积A β。六个月后，我们发现转基因在递送位点以稳定的形式表达，在肝脏和嗅球中有少量异位表达。与EGFP处理的小鼠相比，scFv处理的APPSwe/PS1dE9转基因小鼠的脑A β斑块形成、A β蓄积、AD型病理和认知障碍显著减轻。scFv基因的肌肉内递送被动物良好耐受，在基因表达位点和脑中不引起炎症或微出血，并且在动物中不诱导中和抗体。这些发现表明，外周应用scFv在预防阿尔茨海默病（AD）的发展中是有效和安全的，并且将是用于预防和治疗AD的有希望的非炎症免疫模式。
Anti-beta-amyloid (Aβ) immunotherapy is effective in removing brain Aβ, but has shown to be associated with detrimental effects. We have demonstrated that Adeno-associated virus (AAV)-mediated delivery of an anti-Aβ single chain antibody (scFv) gene was effective in clearing brain Aβ without eliciting any inflammatory side effects in old APPSwe/PS1dE9 transgenic mice. In the present study, we tested the efficacy and safety of intramuscular delivery of the scFv gene in preventing brain Aβ deposition. The scFv gene was intramuscularly delivered to APPSwe/PS1dE9 transgenic mice at 3months of age, prior to Aβ deposition in the brain. Six months later, we found that the transgenes were expressed in a stable form at the delivered sites, with a small amount of ectopic expression in the liver and olfactory bulb. Brain Aβ plaque formation, Aβ accumulation, AD-type pathologies and cognitive impairment were significantly attenuated in scFv-treated APPSwe/PS1dE9 transgenic mice relative to EGFP-treated mice. Intramuscular delivery of scFv gene was well tolerated by the animals, did not cause inflammation or microhemorrhage at the gene expression site and in the brain, and did not induce neutralizing antibodies in the animals. These findings suggest that peripheral application of scFv is effective and safe in preventing the development of Alzheimer’s disease (AD), and would be a promising non-inflammatory immunological modality for prevention and treatment of AD.