Limited clearance of pre-existing amyloid plaques after intracerebral injection of Abeta antibodies in two mouse models of Alzheimer disease.
Recent studies have demonstrated the potential utility of antibodies for the treatment of Alzheimer disease (AD). In transgenic mouse models of AD, peripheral and intracerebral administration of Abeta-specific antibodies reduces amyloid burdens to varied extents. The mechanism may involve clearance of pre-existing amyloid plaques or prevention of new amyloid formation. Here, we have used two transgenic models, the inducible CamKII-ttAxtetAPP/swe/ind (Line 107) and the APPswe/PS1dE9 (Line 85), to test the ability of intracerebral injection of Abeta antibodies to clear amyloid. Because the production of Abeta peptides in the Line 107 model is inducible, whereas production in Line 85 mice is constitutive, we could study the effects of antibody on pre-existing plaques versus continuous plaque formation. In Line 85, injection of antibody resulted in modest but statistically significant reductions in amyloid burden (average, 14%-16%). However, injected antibodies had no effect on amyloid burden in Line 107 under conditions in which the production of Abeta was suppressed, indicating that pre-existing plaques are not rapidly cleared. These results indicate that intracerebral injection of Abeta antibodies produces modest reductions in amyloid deposition in these two models and that the mechanism may involve prevention of amyloid formation rather than clearance of pre-existing plaques.
Tucker
Stina M Fangmark
SM
Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
Borchelt
David R
DR
Troncoso
Juan C
JC
D000544:Alzheimer Disease / Q000473:pathology* / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000276:immunology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006801:Humans; D007116:Immunization, Passive; D007074:Immunoglobulin G / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000187:drug effects*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D007074:Immunoglobulin G; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2