Intracranial adeno-associated virus-mediated delivery of anti-pan amyloid β, amyloid β40, and amyloid β42 single-chain variable fragments attenuates plaque pathology in amyloid precursor protein mice

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