Non-Fc-mediated mechanisms are involved in clearance of amyloid-beta in vivo by immunotherapy.
Transgenic (Tg) mouse models overexpressing amyloid precursor protein (APP) develop senile plaques similar to those found in Alzheimer's disease in an age-dependent manner. Recent reports demonstrated that immunotherapy is effective at preventing or removing amyloid-beta deposits in the mouse models. To characterize the mechanisms involved in clearance, we used antibodies of either IgG1 (10d5) or IgG2b (3d6) applied directly to the brains of 18-month-old Tg2576 or 20-month-old PDAPP mice. Both 10d5 and 3d6 led to clearance of 50% of diffuse amyloid deposits in both animal models within 3 d. Fc receptor-mediated clearance has been shown to be important in an ex vivo assay showing antibody-mediated clearance of plaques by microglia. We now show, using in vivo multiphoton microscopy, that FITC-labeled F(ab')2 fragments of 3d6 (which lack the Fc region of the antibody) also led to clearance of 45% of the deposits within 3 d, similar to the results obtained with full-length 3d6 antibody. This result suggests that direct disruption of plaques, in addition to Fc-dependent phagocytosis, is involved in the antibody-mediated clearance of amyloid-beta deposits in vivo. Dense-core deposits that were not cleared were reduced in size by approximately 30% with full-length antibodies and F(ab')2 fragments 3 d after a topical treatment. Together, these results indicate that clearance of amyloid deposits in vivo may involve, in addition to Fc-dependent clearance, a non-Fc-mediated disruption of plaque structure.
Bacskai
Brian J
BJ
Alzheimer's Disease Research Laboratory, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
Kajdasz
Stephen T
ST
McLellan
Megan E
ME
Games
Dora
D
Seubert
Peter
P
Schenk
Dale
D
Hyman
Bradley T
BT
D000287:Administration, Topical; D000544:Alzheimer Disease / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000276:immunology / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D052160:Benzothiazoles; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005456:Fluorescent Dyes; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D007141:Immunoglobulin Fc Fragments / Q000378:metabolism*; D007167:Immunotherapy; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence / Q000379:methods; D009154:Mutation; D010587:Phagocytosis / Q000276:immunology; D058225:Plaque, Amyloid / Q000187:drug effects / Q000378:metabolism; D013844:Thiazoles
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000906:Antibodies; D052160:Benzothiazoles; D005456:Fluorescent Dyes; D007140:Immunoglobulin Fab Fragments; D007141:Immunoglobulin Fc Fragments; D013844:Thiazoles; C009462:thioflavin T