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Insights into the mechanisms of action of anti-Aß antibodies in Alzheimer’s disease mouse models

Yona Levites^*, Lisa A. Smithson^*, Robert W. Price^*, Rachel S. Dakin^*, Bin Yuan, Michael R. Sierks, Jungsu Kim^*, Eileen McGowan^*, Dana Kim Reed^*, Terrone L. Rosenberry^*, Pritam Das^* and Todd E. Golde^*,1

^* Departments of Neuroscience and Pharmacology, Mayo Clinic, Mayo Clinic College of Medicine, Jacksonville, Florida, USA; and

Department of Chemical and Materials Engineering, Arizona State University, Tempe, Arizona, USA

¹Correspondence: Department of Neuroscience, Mayo Clinic Jacksonville, Birdsall 210, 4500 San Pablo Rd., Jacksonville, FL 32224, USA. E-mail: tgolde{at}mayo.edu

ABSTRACT

A number of hypotheses regarding how anti-Aß antibodies alter amyloid deposition have been postulated, yet there is no consensus as to how Aß immunotherapy works. We have examined the in vivo binding properties, pharmacokinetics, brain penetrance, and alterations in Aß levels after a single peripheral dose of anti-Aß antibodies to both wild-type (WT) and young non-Aß depositing APP and BRI-Aß42 mice. The rapid rise in plasma Aß observed after antibody (Ab) administration is attributable to prolongation of the half-life of Aß bound to the Ab. Only a miniscule fraction of Ab enters the brain, and despite dramatic increases in plasma Aß, we find no evidence that total brain Aß levels are significantly altered. Surprisingly, cerebral spinal fluid Aß levels transiently rise, and when Ab:Aß 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 Aß, these data provide a framework to evaluate proposed mechanisms of Aß attenuation mediated by peripheral administration of an anti-Aß monoclonal antibody (mAb) effective in passive immunization paradigm. Such quantitative data suggest that the mAbs are either indirectly enhancing clearance of Aß or targeting a low abundance aggregation intermediate.—Levites, Y., Smithson, L. A., Price, R. W., Dakin. R. S., Yuan, B., Sierks, M. R., Kim, J., McGowan, E., Reed, D. K., Rosenberry, T. L., Das, P., Golde, T. E. Insights into the mechanisms of action of anti-Aß antibodies in Alzheimer’s disease mouse models.

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