Amyloid-β Immunization Effectively Reduces Amyloid Deposition in FcRγ^-/-Knock-Out Mice

Abstract

Direct immunization with amyloid beta protein (Abeta) and passive transfer of anti-Abeta antibodies reduce Abeta accumulation and attenuate cognitive deficits in transgenic models of Alzheimer's disease (AD). The reduction in Abeta deposition has been proposed to involve microglial phagocytosis of Abeta immune complexes via Fc receptors (FcRs). We have examined the efficacy of Abeta immunization in amyloid precursor protein (APP) transgenic mice crossed into FcR-gamma chain knock-out mice (FcRgamma-/-). As might be expected from previous studies on macrophages, phagocytosis of Abeta immune complexes via FcR was completely impaired in microglia cells isolated from FcRgamma-/- mice. Thus, we immunized APP Tg2576 transgenic mice that were crossed in the FcRgamma-/- background with Abeta1-42 and then analyzed the effect on Abeta accumulation. In APP Tg2576 transgenic mice crossed to FcRgamma-/-, Abeta1-42 immunization significantly attenuated Abeta deposition, as assessed by both biochemical and immunohistological methods. The reduction in Abeta accumulation was equivalent to the reduction in deposition seen in Abeta1-42 immunized, age-matched, FcR-sufficient Tg2576 mice. We conclude that after Abeta immunization, the effects of anti-Abeta antibodies on Abeta deposition in APP Tg2576 transgenic mice are not dependent on FcR-mediated phagocytic events.

Intracerebroventricular amyloid-β antibodies reduce cerebral amyloid angiopathy and associated micro-hemorrhages in aged Tg2576 mice

“…Several studies have proposed a microglial phagocytosis mechanism of amyloid clearance, in which antibodies bound to A␤ also interact with Fc receptors (FcR) on microglial cells to initiate microglial phagocytosis of antibody-bound A␤ and subsequently clear amyloid plaques (10,38,46,54). However, we and others have previously demonstrated a reduction of the parenchymal plaque burden by mechanisms that are independent of microglial function (55)(56)(57)(58). In the current study, microglia were activated with both systemic-and icv-delivered anti-A␤ IgG 1 , and may partially mediate the clearance of parenchymal plaques in both cases.…”

Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain

“…After centrifugation at 4 °C at 100,000 × g for 1 h, the supernatant was collected and stored at −80 °C until assayed. Brain samples were run in triplicate on ELISA plates coated with a monoclonal anti-Aβ1-16 antibody (kindly provided by Dr. William Van Nostrand, Stony Brook University, Stony Brook, NY) and detection was by monoclonal HRP conjugated anti-Aβ1-40 (MM32-13.1.1) and anti-Aβ1-42 (MM40-21.3.1) antibodies (kindly provided by Dr. Christopher Eckman, Mayo Clinic Jacksonville, Jacksonville, CA) [9,28,37]. For standards, Aβ1-40 and Aβ1-42 (Bachem California, Inc., Torrance, CA) were used after a pretreatment with HFIP to prevent fibril formation.…”

Immunization in familial amyloidotic polyneuropathy: counteracting deposition by immunization with a Y78F TTR mutant

“…15 However, a recent study indicated that FcR-mediated uptake of anti-Ab immune complexes is not required for the attenuation of Ab deposition after Ab1-42 immunization in Tg mice. 26 McLaurin et al 27 demonstrated antibody inhibition of Ab fibrillogenesis and cytotoxicity without eliciting an inflammatory response. We speculate that not only FcR-mediated phagocytosis through Ig G but also non-FcR-mediated clearance mechanism for amyloid deposition might as well effectively attenuate TTR deposition in V30M Tg mice.…”