Levites Yona, Jansen Karen, Smithson Lisa A, Dakin Rachel, Holloway Vallie M, Das Pritam, Golde Todd E
Department of Neuroscience, Mayo Clinic, Mayo Clinic College of Medicine, Jacksonville, Florida 32224, USA.
J Neurosci. 2006 Nov 15;26(46):11923-8. doi: 10.1523/JNEUROSCI.2795-06.2006.
Accumulation of amyloid beta protein (Abeta) aggregates is hypothesized to trigger a pathological cascade that causes Alzheimer's disease (AD). Active or passive immunizations targeting Abeta are therefore of great interest as potential therapeutic strategies. We have evaluated the use of recombinant anti-Abeta single-chain variable fragments (scFvs) as a potentially safer form of anti-Abeta immunotherapy. We have generated and characterized three anti-Abeta scFvs that recognize Abeta 1-16, Abeta x-40, or Abeta x-42. To achieve widespread brain delivery, constructs expressing these anti-Abeta scFvs were packaged into adeno-associated virus (AAV) vectors and injected into the ventricles of postnatal day 0 (P0) amyloid precursor protein CRND8-transgenic mice. Intracranial delivery of AAV to neonatal mice resulted in widespread neuronal delivery. In situ expression of each of the anti-Abeta scFvs after intracerebroventricular AAV serotype 1 delivery to P0 pups decreased Abeta deposition by 25-50%. These data suggest that intracranial anti-Abeta scFv expression is an effective strategy to attenuate amyloid deposition. As opposed to transgenic approaches, these studies also establish a "somatic brain transgenic" paradigm to rapidly and cost-effectively evaluate potential modifiers of AD-like pathology in AD mouse models.
淀粉样β蛋白（Aβ）聚集体的积累被认为会引发导致阿尔茨海默病（AD）的病理级联反应。因此，针对Aβ的主动或被动免疫作为潜在的治疗策略备受关注。我们评估了重组抗Aβ单链可变片段（scFv）作为一种潜在更安全的抗Aβ免疫治疗形式的应用。我们制备并鉴定了三种识别Aβ 1-16、Aβ x-40或Aβ x-42的抗Aβ scFv。为实现广泛的脑内递送，将表达这些抗Aβ scFv的构建体包装到腺相关病毒（AAV）载体中，并注射到出生后第0天（P0）的淀粉样前体蛋白CRND8转基因小鼠的脑室中。将AAV颅内递送至新生小鼠导致广泛的神经元递送。向P0幼崽脑室内递送1型AAV后，每种抗Aβ scFv的原位表达使Aβ沉积减少了25%-50%。这些数据表明，颅内抗Aβ scFv表达是减轻淀粉样沉积的有效策略。与转基因方法不同，这些研究还建立了一种“体细胞脑转基因”范式，以快速且经济高效地评估AD小鼠模型中AD样病理的潜在调节因子。
