Antibodies Against Beta-amyloid Reduce Abeta Oligomers, Glycogen Synthase Kinase-3beta Activation and Tau Phosphorylation in Vivo and in Vitro.
From: Department of Medicine, University of California, Los Angeles, California 91343, USA.
Journal of neuroscience research
- Publish Date: Feb 2006
- ISSN: 0360-4012
- Volume: 83
- Issue: 3
- Pages: 374-84
- Medium: Print
- Language: English
- Citation (JAMA): Ma Qiu-Lan, Lim Giselle P, Harris-White Marni E, et al. Antibodies Against Beta-amyloid Reduce Abeta Oligomers, Glycogen Synthase Kinase-3beta Activation and Tau Phosphorylation in Vivo and in Vitro.. J. Neurosci. Res. Feb 2006;83:374-84
Abstract
Although active and passive immunization against the beta-amyloid peptide (Abeta) 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-Abeta (1-15) antibody into the AD HuAPPsw (Tg2576) transgenic mouse model reduced specific oligomeric forms of Abeta, including the dodecamers that correlate with cognitive decline. Interestingly, the reduction of soluble Abeta oligomers, but not insoluble Abeta, significantly correlated with reduced tau phosphorylation by glycogen synthase kinase-3beta (GSK-3beta), a major tau kinase implicated previously in mediating Abeta toxicity. A conformationally-directed antibody against amyloid oligomers (larger than tetramer) also reduced Abeta oligomer-induced activation of GSK3beta and protected human neuronal SH-SY5Y cells from Abeta oligomer-induced neurotoxicity, supporting a role for Abeta 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-3beta, which could be an important strategy for Alzheimer’s disease (AD) therapeutics.
Mesh Headings (Keywords): Amyloid beta-Protein, Amyloid beta-Protein Precursor, Analysis of Variance, Animals, Antibodies, Blotting, Western, Cell Line, Tumor, Cell Survival, Cerebral Cortex, Enzyme Activation, Enzyme Reactivators, Enzyme-Linked Immunosorbent Assay, Female, Glycogen Synthase Kinase 3, Humans, Immunohistochemistry, Male, Mice, Mice, Transgenic, Neuroblastoma, Peptide Fragments, Phosphorylation, Random Allocation, Senile Plaques, Silver Staining, tau Proteins
Check for Full Text / PubMed Unique Identifier (PMID): 16385556
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