Immunization targeting a minor plaque constituent clears β-amyloid and rescues behavioral deficits in an Alzheimer's disease mouse model

NEUROBIOLOGY OF AGING

卷:34

Article

Morales-Corraliza, Jose^1,2  Schmidt, Stephen D.¹  Mazzella, Matthew J.¹  Berger, Jason D.¹  Wilson, Donald A.^3,4,5  Wesson, Daniel W.³  Jucker, Mathias⁶  Levy, Efrat^1,7  Nixon, Ralph A.^1,2,8  Mathews, Paul M.^1,2 

[1] Nathan S Kline Inst Psychiat Res, Ctr Dementia Res, Orangeburg, NY 10962 USA

[2] NYU, Sch Med, Dept Psychiat, New York, NY USA

[3] Nathan S Kline Inst Psychiat Res, Emot Brain Inst, Orangeburg, NY 10962 USA

[4] NYU, Sch Med, Dept Child & Adolescent Psychiat, New York, NY USA

[5] NYU, Ctr Neural Studies, New York, NY USA

[6] Univ Tubingen, Dept Cellular Neurol, Hertie Inst Clin Brain Res, Tubingen, Germany

[7] NYU, Dept Biochem & Mol Pharmacol, Sch Med, New York, NY USA

[8] NYU, Sch Med, Dept Cell Biol, New York, NY 10016 USA

关键词: Alzheimer's disease;    A beta;    Codeposition;    Immunization;    Immunotherapy;   

DOI  :  10.1016/j.neurobiolaging.2012.04.007

来源: Elsevier

【 摘 要 】

Although anti-human beta-amyloid (A beta) immunotherapy clears brain beta-amyloid plaques in Alzheimer's disease (AD), targeting additional brain plaque constituents to promote clearance has not been attempted. Endogenous murine A beta is a minor A beta plaque component in amyloid precursor protein (APP) transgenic AD models, which we show is similar to 3%-8% of the total accumulated A beta in various human APP transgenic mice. Murine A beta codeposits and colocalizes with human A beta in amyloid plaques, and the two A beta species coimmunoprecipitate together from brain extracts. In the human APP transgenic mouse model Tg2576, passive immunization for 8 weeks with a murine-A beta-specific antibody reduced beta-amyloid plaque pathology, robustly decreasing both murine and human A beta levels. The immunized mice additionally showed improvements in two behavioral assays, odor habituation and nesting behavior. We conclude that passive anti-murine A beta immunization clears A beta plaque pathology-including the major human A beta component-and decreases behavioral deficits, arguing that targeting minor endogenous brain plaque constituents can be beneficial, broadening the range of plaque-associated targets for AD therapeutics. (C) 2013 Elsevier Inc. All rights reserved.

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