Bibliographic
This study investigated effects of deglycosylated C-terminal-specific anti-Aβ antibody on amyloid plaque clearance and microglia activation in Tg2576 mice. Past studies have shown vaccinations with Aβ can prevent plaque formation, reduce pre-existing brain amyloid, and protect APP transgenic mice from developing memory impairments. These observations initiated clinical trials in which patients with mild to moderate AD were given an active immunization, but Phase IIa trials were interrupted due to the occurrence of meningoencephalitis in 6% of the patients. Consequently, passive immunization became considered as a possibly safer means of removing Aβ deposits from the brain. Immunization with anti- Aβ monoclonal antibodies has been demonstrated to be an effective means of clearing Aβ plaques and reversing cognitive deficits in Tg mice. However, recent studies have demonstrated potentially harmful aspects of Aβ passive immunotherapy, such as significant increases in cerebral hemorrhage and cerebral amyloid angiopathy in association with increases in vascular leakage. Microglial activation has been shown surrounding amyloid-containing blood vessels following systemic passive immunization and could potentially be one of the mechanisms that increase the likelihood of microhemorrhage. This study investigated the efficacy of a deglycosylated antibody with decreased affinity for the Fcγ receptor for its ability to eliminate Aβ from the brain without increasing microglial activation. Results show that deglycosylated 2H6 antibody had lower affinity for several murine Fcγ receptors and human complement than intact 2H6 without a change in affinity for Aß, with reductions in both diffuse and compact deposits and no increase in Fcγ-receptor II/III or the microglial activation marker CD45. These findings suggest that antibodies with reduced effector functions may clear amyloid without concomitant immune activation when tested as immunotherapy for Alzheimer's disease.