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

Soluble oligomeric amyloid beta (oA beta) 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 oA beta 1-42 neurotoxicity is not fully understood. Here, we showed that oA beta but not fibrillar A beta was neurotoxic, and microglia activated with unmethylated DNA CpG motif (CpG), a ligand for Toll-like receptor 9, attenuated oA beta 1-42 neurotoxicity in primary neuron-microglia co-cultures. CpG enhanced microglial clearance of oA beta 1-42 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 oA beta 1-42 and the impairment of associative learning in Tg2576 mouse model of AD. We propose that CpG may he an effective therapeutic strategy for limiting oA beta 1-42 neurotoxicity in AD. (Am J Pathol 2009, 175:2121-2132; DOI: 10.2353/ajpath.2009.090418)