Published online before print October 15, 2009

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(American Journal of Pathology. 2009;175:2121-2132.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.090418

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

Yukiko Doi^*, Tetsuya Mizuno^*, Yuki Maki^*, Shijie Jin^*, Hiroyuki Mizoguchi, Masayoshi Ikeyama, Minoru Doi, Makoto Michikawa, Hideyuki Takeuchi^* and Akio Suzumura^*

From the Department of Neuroimmunology^* and the Futuristic Environmental Simulation Center, Research Institute of Environmental Medicine, Nagoya University, Nagoya; the Department of Materials Science and Engineering, Nagoya Institute of Technology, Nagoya; and the Department of Alzheimer’s Disease Research, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Aichi, Japan

Soluble oligomeric amyloid β (oAβ) 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 oAβ1-42 neurotoxicity is not fully understood. Here, we showed that oAβ but not fibrillar Aβ was neurotoxic, and microglia activated with unmethylated DNA CpG motif (CpG), a ligand for Toll-like receptor 9, attenuated oAβ1-42 neurotoxicity in primary neuron-microglia co-cultures. CpG enhanced microglial clearance of oAβ1-42 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 oAβ1-42 and the impairment of associative learning in Tg2576 mouse model of AD. We propose that CpG may be an effective therapeutic strategy for limiting oAβ1-42 neurotoxicity in AD.

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