Insights into the mechanisms of action of anti-Abeta antibodies in Alzheimer's disease mouse models.
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.
Levites
Yona
Y
Department of Neuroscience, Mayo Clinic, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.
Smithson
Lisa A
LA
Price
Robert W
RW
Dakin
Rachel S
RS
Yuan
Bin
B
Sierks
Michael R
MR
Kim
Jungsu
J
McGowan
Eileen
E
Reed
Dana Kim
DK
Rosenberry
Terrone L
TL
Das
Pritam
P
Golde
Todd E
TE
D000544:Alzheimer Disease / Q000276:immunology* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000097:blood / Q000134:cerebrospinal fluid / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood / Q000276:immunology* / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007116:Immunization, Passive; D051379:Mice; D008822:Mice, Transgenic
D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal