Amyloid-b Immunization Effectively Reduces Amyloid Deposition in FcR__ Knock-Out Mice.pdf

Cellular/Molecular Amyloid-
Immunization Effectively Reduces Amyloid Deposition in FcR
/
Knock-Out Mice Pritam Das, Victor Howard, Nicole Loosbrock, Dennis Dickson, M. Paul Murphy, and Todd E. Golde Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224 Direct immunization with amyloid
protein (A
) and passive transfer of anti-A
antibodies reduce A
accumulation and attenuate cognitive deficits in transgenic models of Alzheimer’s disease (AD). The reduction in A
deposition has been proposed to involve microglial phagocytosis of A
immune complexes via Fc receptors (FcRs). We have examined the efficacy of A
immunization in amyloid precursor protein (APP) transgenic mice crossed into FcR- chain knock-out mice (FcR
/
). As might be expected from previous studies on macrophages, phagocy- tosis of A
immune complexes via FcR was completely impaired in microglia cells isolated from FcR
/
mice. Thus, we immunized APP Tg2576 transgenic mice that were crossed in the FcR
/
background with A
1– 42 and then analyzed the effect on A
accumulation. In APP Tg2576 transgenic mice crossed to FcR
/
, A
1– 42 immunization significantly attenuated A
deposition, as assessed by both biochemical and immunohistological methods. The reduction in A
accumulation was equivalent to the reduction in deposition seen in A
1– 42 immunized, age-matched, FcR-sufficient Tg2576 mice. We conclude that after A
immunization, the effects of anti-A
antibodies on A
deposition in APP Tg2576 transgenic mice are not dependent on FcR-mediated phagocytic events. Key words: Alzheimer’s disease;
-amyloid protein; Fc receptor; scavenger receptor; microglia; vaccination Introduction Multiple strategies targeting the accumulation of amyloid
(A
) peptides, the primary constituent of senile plaques in Alzheimer’s disease (AD) (Selkoe, 1997; Golde et al., 2000), have been actively pursued as a potential therapeutic target for the treatment of AD. Recent studies have shown that immuniza