Passive Immunization against Pyroglutamate-3 Amyloid-β Reduces Plaque Burden in Alzheimer-Like Transgenic Mice: A Pilot Study

被引：63
作者：
Frost, Jeffrey L. [1 ]
Liu, Bin [1 ]
Kleinschmidt, Martin [2 ]
Schilling, Stephan [2 ]
Demuth, Hans-Ulrich [2 ]
Lemere, Cynthia A. [1 ]
机构：
[1] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Dis, Boston, MA 02115 USA
[2] Probiodrug AG, Halle, Saale, Germany
来源：
NEURODEGENERATIVE DISEASES | 2012年 / 10卷 / 1-4期
关键词：
Alzheimer's disease; Pyroglutamate-3; amyloid-beta; Monoclonal antibody; Immunotherapy; Transgenic mice; A-BETA; DISEASE; DEPOSITION; PEPTIDES; MUTATION;
D O I：
10.1159/000335913
中图分类号：
R74 [神经病学与精神病学];
学科分类号：
摘要：
Background: N-terminally truncated and modified pyroglutamate-3 amyloid-beta protein (pE3-A beta) is present in most, if not all, cerebral plaque and vascular amyloid deposits in human Alzheimer's disease (AD). pE3-A beta deposition is also found in AD-like transgenic (tg) mouse brain, albeit in lesser quantities than general A beta. pE3-A beta resists degradation, is neurotoxic, and may act as a seed for A beta aggregation. Objective: We sought to determine if pE3-A beta removal by passive immunization with a highly specific monoclonal antibody (mAb) impacts pathogenesis in a mouse model of Alzheimer's amyloidosis. Methods: APPswe/PS1 Delta E9 tg mice were given weekly intraperitoneal injections of a new anti-pE3-A beta mAb (mAb07/1) or PBS from 5.8 to 13.8 months of age (prevention) or from 23 to 24.7 months of age (therapeutic). Multiple forms of cerebral A beta were quantified pathologically and biochemically. Gliosis and microhemorrhage were examined. Results: Chronic passive immunization with an anti-pE3-A beta mAb significantly reduced total plaque deposition and appeared to lower gliosis in the hippocampus and cerebellum in both the prevention and therapeutic studies. Insoluble A beta levels in hemibrain homogenates were not significantly different between immunized and control mice. Microhemorrhage was not observed with anti-pE3-A beta immunotherapy. Conclusions: Selective removal of pE3-A beta lowered general A beta plaque deposition suggesting a pro-aggregation or seeding role for pE3-A beta. Copyright (C) 2012 S. Karger AG, Basel
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页码：265 / 270
页数：6
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