TY - JOUR
T1 - Insights into the mechanisms of action of anti-Aβ antibodies in Alzheimer's disease mouse models
AU - Levites, Yona
AU - Smithson, Lisa A.
AU - Price, Robert W.
AU - Dakin, Rachel S.
AU - Yuan, Bin
AU - Sierks, Michael R.
AU - Kim, Jungsu
AU - McGowan, Eileen
AU - Dana, Kim Reed
AU - Rosenberry, Terrone L.
AU - Das, Pritam
AU - Golde, Todd E.
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2006/12
Y1 - 2006/12
N2 - A number of hypotheses regarding how anti-Aβ antibodies alter amyloid deposition have been postulated, yet there is no consensus as to how Aβ immunotherapy works. We have examined the in vivo binding properties, pharmacokinetics, brain penetrance, and alterations in Aβ levels after a single peripheral dose of anti-Aβ antibodies to both wild-type (WT) and young non-Aβ depositing APP and BRI-Aβ42 mice. The rapid rise in plasma Aβ observed after antibody (Ab) administration is attributable to prolongation of the half-life of Aβ bound to the Ab. Only a miniscule fraction of Ab enters the brain, and despite dramatic increases in plasma Aβ, we find no evidence that total brain Aβ levels are significantly altered. Surprisingly, cerebral spinal fluid Aβ levels transiently rise, and when Ab:Aβ 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 Aβ, these data provide a framework to evaluate proposed mechanisms of Aβ attenuation mediated by peripheral administration of an anti-Aβ monoclonal antibody (mAb) effective in passive immunization paradigm. Such quantitative data suggest that the mAbs are either indirectly enhancing clearance of Aβ or targeting a low abundance aggregation intermediate.
AB - A number of hypotheses regarding how anti-Aβ antibodies alter amyloid deposition have been postulated, yet there is no consensus as to how Aβ immunotherapy works. We have examined the in vivo binding properties, pharmacokinetics, brain penetrance, and alterations in Aβ levels after a single peripheral dose of anti-Aβ antibodies to both wild-type (WT) and young non-Aβ depositing APP and BRI-Aβ42 mice. The rapid rise in plasma Aβ observed after antibody (Ab) administration is attributable to prolongation of the half-life of Aβ bound to the Ab. Only a miniscule fraction of Ab enters the brain, and despite dramatic increases in plasma Aβ, we find no evidence that total brain Aβ levels are significantly altered. Surprisingly, cerebral spinal fluid Aβ levels transiently rise, and when Ab:Aβ 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 Aβ, these data provide a framework to evaluate proposed mechanisms of Aβ attenuation mediated by peripheral administration of an anti-Aβ monoclonal antibody (mAb) effective in passive immunization paradigm. Such quantitative data suggest that the mAbs are either indirectly enhancing clearance of Aβ or targeting a low abundance aggregation intermediate.
KW - Amyloid deposits
KW - Immune complex
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U2 - 10.1096/fj.06-6463fje
DO - 10.1096/fj.06-6463fje
M3 - Article
C2 - 17068112
AN - SCOPUS:33845639102
VL - 20
SP - E2002-E2014
JO - The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
JF - The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
SN - 0892-6638
IS - 14
ER -