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A number of hypotheses regarding how anti-Abeta antibodies alter amyloid deposition have been postulated, yet there is no consensus as to how Abeta immunotherapy works. We have examined the in vivo binding properties, pharmacokinetics, brain penetrance, and alterations in Abeta levels after a single peripheral dose of anti-Abeta antibodies to both wild-type (WT) and young non-Abeta depositing APP and BRI-Abeta42 mice. The rapid rise in plasma Abeta observed after antibody (Ab) administration is attributable to prolongation of the half-life of Abeta bound to the Ab. Only a miniscule fraction of Ab enters the brain, and despite dramatic increases in plasma Abeta, we find no evidence that total brain Abeta levels are significantly altered. Surprisingly, cerebral spinal fluid Abeta levels transiently rise, and when Ab:Abeta complex is directly injected into the lateral ventricles of mice, it is rapidly cleared from the brain into the plasma where it remains stable. When viewed in context of daily turnover of Abeta, these data provide a framework to evaluate proposed mechanisms of Abeta attenuation mediated by peripheral administration of an anti-Abeta monoclonal antibody (mAb) effective in passive immunization paradigm. Such quantitative data suggest that the mAbs are either indirectly enhancing clearance of Abeta or targeting a low abundance aggregation intermediate.

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