Microglia activated with the toll-like receptor 9 ligand CpG attenuate oligomeric amyloid {beta} neurotoxicity in in vitro and in vivo models of Alzheimer's disease.
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.
Doi
Yukiko
Y
Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Japan.
Mizuno
Tetsuya
T
Maki
Yuki
Y
Jin
Shijie
S
Mizoguchi
Hiroyuki
H
Ikeyama
Masayoshi
M
Doi
Minoru
M
Michikawa
Makoto
M
Takeuchi
Hideyuki
H
Suzumura
Akio
A
D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003214:Conditioning, Classical; D018899:CpG Islands; D051547:Heme Oxygenase-1 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008568:Memory / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D061965:Matrix Metalloproteinase Inhibitors; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D051217:Toll-Like Receptor 9; C075222:amyloid beta-protein (1-42); D051547:Heme Oxygenase-1; D020780:Matrix Metalloproteinase 9