Accumulation of amyloid β protein (Aβ) aggregates is hypothesized to trigger a pathological cascade that causes Alzheimer's disease (AD). Active or passive immunizations targeting Aβ are therefore of great interest as potential therapeutic strategies. We have evaluated the use of recombinant anti-Aβ single-chain variable fragments (scFvs) as a potentially safer form of anti-Aβ immunotherapy. We have generated and characterized three anti-Aβ scFvs that recognize Aβ1-16, Aβx-40, or Aβx-42. To achieve widespread brain delivery, constructs expressing these anti-Aβ 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-Aβ scFvs after intracerebroventricular AAV serotype 1 delivery to P0 pups decreased Aβ deposition by 25-50%. These data suggest that intracranial anti-Aβ 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.
- Adeno-associated virus
- Alzheimer's disease
- Amyloid; Aβ
- Single-chain variable fragments
ASJC Scopus subject areas