Passive amyloid immunotherapy clears amyloid and transiently activates microglia in a transgenic mouse model of amyloid deposition.
The role of microglia in the removal of amyloid deposits after systemically administered anti-Abeta antibodies remains unclear. In the current study, we injected Tg2576 APP transgenic mice weekly with an anti-Abeta antibody for 1, 2, or 3 months such that all mice were 22 months at the end of the study. In mice immunized for 3 months, we found an improvement in alternation performance in the Y maze. Histologically, we were able to detect mouse IgG bound to congophilic amyloid deposits in those mice treated with the anti-Abeta antibody but not in those treated with a control antibody. We found that Fcgamma receptor expression on microglia was increased after 1 month of treatment, whereas CD45 was increased after 2 months of treatment. Associated with these microglial changes was a reduction in both diffuse and compact amyloid deposits after 2 months of treatment. Interestingly, the microglia markers were reduced to control levels after 3 months of treatment, whereas amyloid levels remained reduced. Serum Abeta levels and anti-Abeta antibody levels were elevated to similar levels at all three survival times in mice given anti-Abeta injections rather than control antibody injections. These data show that the antibody is able to enter the brain and bind to the amyloid deposits, likely opsonizing the Abeta and resulting in Fcgamma receptor-mediated phagocytosis. Together with our earlier work, our data argue that all proposed mechanisms of anti-Abeta antibody-mediated amyloid removal can be simultaneously active.
Wilcock
Donna M
DM
Alzheimer's Research Laboratory, University of South Florida, Tampa, Florida 33612, USA.
Rojiani
Amyn
A
Rosenthal
Arnon
A
Levkowitz
Gil
G
Subbarao
Sangeetha
S
Alamed
Jennifer
J
Wilson
David
D
Wilson
Nedda
N
Freeman
Melissa J
MJ
Gordon
Marcia N
MN
Morgan
Dave
D
D000682:Amyloid / Q000276:immunology / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000276:immunology / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000686:Amyloidosis / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D007116:Immunization, Passive / Q000379:methods*; D007074:Immunoglobulin G / Q000378:metabolism; D007150:Immunohistochemistry; D017493:Leukocyte Common Antigens / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017452:Receptors, IgG / Q000378:metabolism; D013997:Time Factors
D000682:Amyloid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000911:Antibodies, Monoclonal; D015415:Biomarkers; D007074:Immunoglobulin G; D017452:Receptors, IgG; D017493:Leukocyte Common Antigens