Microglia Activated with the Toll-Like Receptor 9 Ligand CpG Attenuate Oligomeric Amyloid β Neurotoxicity in in Vitro and in Vivo Models of Alzheimer’s Disease
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Soluble oligomeric amyloid beta (oAbeta) 1-42 causes synaptic dysfunction and neuronal injury in Alzheimer's disease (AD). Although accumulation of microglia around senile plaques is a hallmark of AD pathology, the role of microglia in oAbeta1-42 neurotoxicity is not fully understood. Here, we showed that oAbeta but not fibrillar Abeta was neurotoxic, and microglia activated with unmethylated DNA CpG motif (CpG), a ligand for Toll-like receptor 9, attenuated oAbeta1-42 neurotoxicity in primary neuron-microglia co-cultures. CpG enhanced microglial clearance of oAbeta1-42 and induced higher levels of the antioxidant enzyme heme oxygenase-1 in microglia without producing neurotoxic molecules such as nitric oxide and glutamate. Among subclasses of CpGs, class B and class C activated microglia to promote neuroprotection. Moreover, intracerebroventricular administration of CpG ameliorated both the cognitive impairments induced by oAbeta1-42 and the impairment of associative learning in Tg2576 mouse model of AD. We propose that CpG may be an effective therapeutic strategy for limiting oAbeta1-42 neurotoxicity in AD.
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Responses to unmethylated CpG DNA have been detected in CNS cells.
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From An innate immune response to adeno-associated virus genomes decreases cortical dendritic complexity and disrupts synaptic transmission (2024) · cites this paper as [49]
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- Authors
- Doi, Y., Mizuno, T., Maki, Y., Jin, S., Mizoguchi, H., Ikeyama, M., Doi, M., Michikawa, M., Takeuchi, H., & Suzumura, A.
- Affiliations
- Research Institute of Environmental Medicine, Nagoya University (JP)
- Nagoya Institute of Technology (JP)
- National Center for Geriatrics and Gerontology (JP)
- Corresponding author
- Mizuno, Tetsuya
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2009-11
- Volume
- 175
- Issue
- 5
- Pages
- 2121-2132
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC2774075
- OpenAlex
- W2169028987
- Cited by
- 135
- References
- 52
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 6 · 2023: 5 · 2022: 5 · 2021: 12 · 2020: 3 · 2019: 5 · 2018: 8 · 2017: 7 · 2016: 6 · 2015: 9 · 2014: 12 · 2013: 12 · 2012: 14
- FWCI
- 8.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Biomedical Innovation
- Ministry of Education, Culture, Sports, Science and Technology
- Ministry of Health, Labour and Welfare
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- microglia, amyloid-beta oligomers, Alzheimer's disease, CpG oligodeoxynucleotides, TLR9, neuroprotection, heme oxygenase-1, amyloid clearance, Tg2576 mice, cognitive impairment, associative learning, neuroinflammation
- MeSH terms
- Alzheimer Disease, Animals, Behavior, Animal, Cells, Cultured, Conditioning, Classical, Memory, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Neuropsychological Tests, Peptide Fragments, Amyloid beta-Peptides, Reactive Oxygen Species, Microglia, CpG Islands, Coculture Techniques, Matrix Metalloproteinase 9, Toll-Like Receptor 9, Mice, Heme Oxygenase-1, Matrix Metalloproteinase Inhibitors
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