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Antibodies against β‐amyloid reduce aβ oligomers, glycogen synthase kinase‐3β activation and τ phosphorylation in vivo and in vitro
Author(s) -
Ma QiuLan,
Lim Giselle P.,
HarrisWhite Marni E.,
Yang Fusheng,
Ambegaokar Surendra S.,
Ubeda Oliver J.,
Glabe Charles G.,
Teter Bruce,
Frautschy Sally A.,
Cole Greg M.
Publication year - 2005
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.20734
Subject(s) - gsk 3 , oligomer , neurotoxicity , glycogen synthase , chemistry , phosphorylation , kinase , genetically modified mouse , biochemistry , amyloid (mycology) , microbiology and biotechnology , transgene , toxicity , biology , inorganic chemistry , organic chemistry , gene
Although active and passive immunization against the β‐amyloid peptide (Aβ) 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‐Aβ (1–15) antibody into the AD HuAPPsw (Tg2576) transgenic mouse model reduced specific oligomeric forms of Aβ, including the dodecamers that correlate with cognitive decline. Interestingly, the reduction of soluble Aβ oligomers, but not insoluble Aβ, significantly correlated with reduced τ phosphorylation by glycogen synthase kinase‐3β (GSK‐3β), a major τ kinase implicated previously in mediating Aβ toxicity. A conformationally‐directed antibody against amyloid oligomers (larger than tetramer) also reduced Aβ oligomer‐induced activation of GSK3β and protected human neuronal SH‐SY5Y cells from Aβ oligomer‐induced neurotoxicity, supporting a role for Aβ oligomers in human τ kinase activation. These data suggest that antibodies that are highly specific for toxic oligomer subspecies may reduce toxicity via reduction of GSK‐3β, which could be an important strategy for Alzheimer's disease (AD) therapeutics. © 2005 Wiley‐Liss, Inc.