Antibodies against β‐amyloid reduce aβ oligomers, glycogen synthase kinase‐3β activation and τ phosphorylation in vivo and in vitro
Abstract
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.
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Activities of GSK3 and PAR-1/MARKs are often associated with tau detachment from microtubules and Aβ-induced augmentation of tau toxicity.
“the activities of two major tau kinases, GSK3 and PAR-1/microtubule affinity-regulating kinases (MARKs), are often associated with tau detachment from microtubules and Aβ-induced augmentation of tau toxicity [37, 39, 43–45].”
In cellular and animal models, co-expression of Aβ augments tau phosphorylation at these sites and increases the levels of active GSK3 and PAR-1/MARK.
“In cellular and animal models, co-expression of Aβ augments tau phosphorylation at these sites and increases the levels of active GSK3 and PAR-1/MARK [2, 35–41, 43, 44].”
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- Authors
- Ma, Q., Lim, G. P., Harris‐White, M. E., Yang, F., Ambegaokar, S. S., Ubeda, O. J., Glabe, C. G., Teter, B., Frautschy, S. A., & Cole, G. M.
- Affiliations
- University of California, Los Angeles (US)
- University of California, Irvine (US)
- Corresponding author
- Cole, Greg M.
- ORCID
- Venue
- Journal of Neuroscience Research
- Publisher
- Wiley
- Published
- 2005-12-29
- Volume
- 83
- Issue
- 3
- Pages
- 374-384
- ISSN
- 0360-4012 (ISSN-L)
- 1097-4547
- OpenAlex
- W2133064784
- Cited by
- 126
- References
- 6
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 3 · 2022: 2 · 2021: 4 · 2020: 2 · 2019: 6 · 2018: 5 · 2017: 1 · 2016: 5 · 2015: 4 · 2014: 11 · 2013: 6 · 2012: 8
- FWCI
- 6.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neuroscience Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P50AG016570, R01AG010685, R01AG021975, R01AG022080)
- National Institute of Neurological Disorders and Stroke (R01NS043946)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- amyloid-beta oligomers, anti-amyloid antibodies, passive immunization, glycogen synthase kinase-3β, tau phosphorylation, Alzheimer's disease, amyloid plaques, Tg2576 mice, neuroprotection, SH-SY5Y cells, cognitive decline
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Analysis of Variance, Animals, Antibodies, Cell Survival, Cerebral Cortex, Enzyme Activation, Enzyme Reactivators, Enzyme-Linked Immunosorbent Assay, Female, Humans, Immunohistochemistry, Male, Mice, Transgenic, Neuroblastoma, Peptide Fragments, Phosphorylation, Random Allocation, Blotting, Western, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Silver Staining, tau Proteins, Glycogen Synthase Kinase 3, Cell Line, Tumor, Mice, Plaque, Amyloid, In Vitro Techniques
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