Journal
JOURNAL OF NEUROSCIENCE RESEARCH
Volume 83, Issue 3, Pages 374-384Publisher
WILEY
DOI: 10.1002/jnr.20734
Keywords
Alzheimer's disease; passive immunization; immunoneutralization; amyloid; neurofibrillary tangles
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Funding
- NIA NIH HHS [R01 AG022080, R01 AG10685, R01 AG010685, R01 AG021975, P50 AG016570] Funding Source: Medline
- NINDS NIH HHS [R01 NS043946, R01 NS43946] Funding Source: Medline
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Although active and passive immunization against the beta-amyloid peptide (A beta) of amyloid plaque-bearing transgenic mice markedly reduces amyloid plaque deposition and improves cognition, the mechanisms of neuroprotection and impact on toxic oligomer species are not understood. We demonstrate that compared to control IgG2b, passive immunization with intracerebroventricular (icv) anti-A beta (1-15) antibody into the AD HuAPPsw (Tg2576) transgenic mouse model reduced specific oligomeric forms of A beta, including the dodecamers; that correlate with cognitive decline. Interestingly, the reduction of soluble A beta oligomers, but not insoluble A beta, significantly correlated with reduced tau phosphorylation by glycogen synthase kinase-3 beta (GSK-3 beta), a major tau kinase implicated previously in mediating A beta toxicity. A conformationally-directed antibody against amyloid oligomers (larger than tetramer) also reduced A beta oligomer-induced activation of GSK3 beta and protected human neuronal SH-SY5Y cells from A beta oligomer-induced neurotoxicity, supporting a role for A beta oligomers in human tau kinase activation. These data suggest that antibodies that are highly specific for toxic oligomer subspecies may reduce toxicity via reduction of GSK-3 beta, which could be an important strategy for Alzheimer's disease (AD) therapeutics. (c) 2005Wiley-Liss, Inc.
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