Intracranial administration of deglycosylated C-terminal-specific anti-Abeta antibody efficiently clears amyloid plaques without activating microglia in amyloid-depositing transgenic mice.
BACKGROUND
Antibodies against the Ass peptide clear Ass deposits when injected intracranially. Deglycosylated antibodies have reduced effector functions compared to their intact counterparts, potentially avoiding immune activation.


METHODS
Deglycosylated or intact C-terminal specific high affinity anti-Abeta antibody (2H6) were intracranially injected into the right frontal cortex and hippocampus of amyloid precursor protein (APP) transgenic mice. The untreated left hemisphere was used to normalize for the extent of amyloid deposition present in each mouse. Control transgenic mice were injected with an antibody against a drosophila-specific protein (amnesiac). Tissues were examined for brain amyloid deposition and microglial responses 3 days after the injection.


RESULTS
The deglycosylated 2H6 antibody had lower affinity for several murine Fcgamma receptors and human complement than intact 2H6 without a change in affinity for Ass. Immunohistochemistry for Abeta and thioflavine-S staining revealed that both diffuse and compact deposits were reduced by both antibodies. In animals treated with the intact 2H6 antibody, a significant increase in Fcgamma-receptor II/III immunostaining was observed compared to animals treated with the control IgG antibody. No increase in Fcgamma-receptor II/III was found with the deglycosylated 2H6 antibody. Immunostaining for the microglial activation marker CD45 demonstrated a similar trend.


CONCLUSIONS
These findings suggest that the deglycosylated 2H6 is capable of removing both compact and diffuse plaques without activating microglia. Thus, antibodies with reduced effector functions may clear amyloid without concomitant immune activation when tested as immunotherapy for Alzheimer's disease.
Carty
Niki C
NC
Alzheimer's Research Laboratory, University of South Florida, Department of Molecular Pharmacology and Physiology, 12901 Bruce B Downs Blvd, Tampa, FL 33612, USA. ncarty@hsc.usf.edu
Wilcock
Donna M
DM
Rosenthal
Arnon
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Grimm
Jan
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Pons
Jaume
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Ronan
Victoria
V
Gottschall
Paul E
PE
Gordon
Marcia N
MN
Morgan
Dave
D