Cited by 135Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNeurological Disease Mechanisms and Treatments

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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Doi, Yukiko, Mizuno, Tetsuya, Maki, Yuki, Jin, Shijie, Mizoguchi, Hiroyuki, Ikeyama, Masayoshi, Doi, Minoru, Michikawa, Makoto +2 more·2009·The American Journal of Pathology

Abstract

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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  1. Xie Z, Wei M, Morgan TE, Fabrizio P, Han D, Finch CE, Longo VD: Peroxynitrite mediates neurotoxicity of amyloid ␤-peptide1-42-and li- popolysaccharide-activated microglia. J Neurosci 2002, 22:3484 -3492
  2. Krug A, Rothenfusser S, Hornung V, Jahrsdorfer B, Blackwell S, Ballas ZK, Endres S, Krieg AM, Hartmann G: Identification of CpG oligonucleotide sequences with high induction of IFN-␣/␤ in plasma- cytoid dendritic cells. Eur J Immunol 2001, 31:2154 -2163

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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)
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
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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