An anti-pyroglutamate-3 A beta vaccine reduces plaques and improves cognition in APPswe/PS1 Delta E9 mice

摘要

Pyroglutamate-3 amyloid-beta (pGlu-3 A beta) is an N-terminally truncated Ab isoform likely playing a decisive role in Alzheimer's disease pathogenesis. Here, we describe a prophylactic passive immunization study in APPswe/PS1 Delta E9 mice using a novel pGlu-3 A beta immunoglobulin G1 (IgG1) monoclonal antibody, 07/1 (150 and 500 mu g, intraperitoneal, weekly) and compare its efficacy with a general A beta IgG1 monoclonal antibody, 3A1 (200 mu g, intraperitoneal, weekly) as a positive control. After 28 weeks of treatment, plaque burden was reduced and cognitive performance of 07/1-immunized Tg mice, especially at the higher dose, was normalized to wild-type levels in 2 hippocampal-dependent tests and partially spared compared with phosphate-buffered saline-treated Tg mice. Mice that received 3A1 had reduced plaque burden but showed no cognitive benefit. In contrast with 3A1, treatment with 07/1 did not increase the concentration of A beta in plasma, suggesting different modes of A beta plaque clearance. In conclusion, A beta plaque burden and preventing cognitive decline in the clinical setting. Targeting this pathologically modified form of A beta thereby is unlikely to interfere with potential physiologic function(s) of A beta that have been proposed. (C) 2015 Elsevier Inc. All rights reserved.