Non-Fc-Mediated Mechanisms Are Involved in Clearance of Amyloid-beta In Vivo by Immunotherapy

• Published in: The Journal of neuroscience 2002-09, Vol.22 (18), p.7873-7878
• Main Authors: Bacskai, Brian J, Kajdasz, Stephen T, McLellan, Megan E, Games, Dora, Seubert, Peter, Schenk, Dale, Hyman, Bradley T
• Format: Article
• Language: English
• Subjects: Administration, Topical; Alzheimer Disease - immunology; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer Disease - therapy; Amyloid beta-Peptides - immunology; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Animals; Antibodies - administration & dosage; Brain - metabolism; Brain - pathology; Disease Models, Animal; Fluorescent Dyes; Humans; Immunoglobulin Fab Fragments - pharmacology; Immunoglobulin Fc Fragments - metabolism; Immunotherapy; Mice; Mice, Transgenic; Microscopy, Fluorescence - methods; Mutation; Phagocytosis - immunology; Plaque, Amyloid - drug effects; Plaque, Amyloid - metabolism; Thiazoles
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.22-18-07873.2002

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.