Insights into the mechanisms of action of anti-Aβ antibodies in Alzheimer's disease mouse models

A number of hypotheses regarding how anti-A beta antibodies alter amyloid deposition have been postulated, yet there is no consensus as to how A beta immunotherapy works. We have examined the in vivo binding properties, pharmacokinetics, brain penetrance, and alterations in A beta levels after a single peripheral dose of anti-A beta antibodies to both wild-type (WT) and young non-A beta depositing APP and BRI-A beta 42 mice. The rapid rise in plasma A beta observed after antibody (Ab) administration is attributable to prolongation of the half-life of A beta bound to the Ab. Only a miniscule fraction of Ab enters the brain, and despite dramatic increases in plasma A beta, we find no evidence that total brain A beta levels are significantly altered. Surprisingly, cerebral spinal fluid A beta levels transiently rise, and when Ab:A beta 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 A beta, these data provide a framework to evaluate proposed mechanisms of A beta attenuation mediated by peripheral administration of an anti-A beta monoclonal antibody (mAb) effective in passive immunization paradigm. Such quantitative data suggest that the mAbs are either indirectly enhancing clearance of A beta or targeting a low abundance aggregation intermediate.