Department of Human Physiology, Center for Neuroscience, Flinders University, Adelaide 5042, Australia.
Brain Behav Immun. 2010 Nov;24(8):1281-93. doi: 10.1016/j.bbi.2010.05.010. Epub 2010 Jun 2.
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 APP(Swe)/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 APP(Swe)/PS1dE9 transgenic mice at 3 months 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 APP(Swe)/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.
抗β-淀粉样蛋白（Aβ）免疫疗法在清除脑内 Aβ 方面有效，但已显示出与有害作用相关。我们已经证明，腺相关病毒（AAV）介导的抗 Aβ 单链抗体（scFv）基因的传递可有效清除脑内 Aβ，而在老年 APP（Swe）/PS1dE9 转基因小鼠中没有引起任何炎症副作用。在本研究中，我们测试了肌内递送 scFv 基因预防脑内 Aβ沉积的功效和安全性。在脑内 Aβ 沉积之前，将 scFv 基因肌内递送至 APP（Swe）/PS1dE9 转基因小鼠。6 个月后，我们发现转基因在递送部位以稳定的形式表达，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 APP（Swe）/PS1dE9 转基因小鼠的脑 Aβ 斑块形成、Aβ 积累、AD 型病理和认知障碍明显减轻。scFv 基因的肌内递送被动物很好地耐受，在基因表达部位和脑内不会引起炎症或微出血，也不会在动物中诱导中和抗体。这些发现表明，外周应用 scFv 可有效且安全地预防阿尔茨海默病（AD）的发生，并且可能是一种有前途的非炎症性免疫治疗方法，用于 AD 的预防和治疗。
