Chronic Amyloid β Oligomer Infusion Evokes Sustained Inflammation and Microglial Changes in the Rat Hippocampus via NLRP3

Microglia are instrumental for recognition and elimination of amyloid beta(1-42) oligomers (A beta Os), but the long-term consequences of A beta O-induced inflammatory changes in the brain are unclear. Here, we explored microglial responses and transciptome-level inflammatory signatures in the rat hippocampus after chronic A beta O challenge. Middle-aged Long Evans rats received intracerebroventricular infusion of A beta O or vehicle for 4 weeks, followed by treatment with artificial CSF or MCC950 for the subsequent 4 weeks. AbO infusion evoked a sustained inflammatory response including activation of NF-kappa B, triggered microglia activation and increased the expression of pattern recognition and phagocytic receptors. A beta(1-42) plaques were not detectable likely due to microglial elimination of infused oligomers. In addition, we found upregulation of neuronal inhibitory ligands and their cognate microglial receptors, while downregulation of Esr1 and Scn1a, encoding estrogen receptor alpha and voltage-gated sodium-channel Na(v) 1.1, respectively, was observed. These changes were associated with impaired hippocampus-dependent spatial memory and resembled early neurological changes seen in Alzheimer's disease. To investigate the role of inflammatory actions in memory deterioration, we performed MCC950 infusion, which specifically blocks the NLRP3 inflammasome. MCC950 attenuated A beta O-evoked microglia reactivity, restored expression of neuronal inhibitory ligands, reversed downregulation of ER alpha, and abolished memory impairments. Furthermore, MCC950 abrogated A beta O-invoked reduction of serum IL-10. These findings provide evidence that in response to AbO infusion microglia change their phenotype, but the resulting inflammatory changes are sustained for at least one month after the end of AbO challenge. Lasting NLRP3-driven inflammatory alterations and altered hippocampal gene expression contribute to spatial memory decline. This article is part of a Special Issue entitled: Microglia-Neuron interactions in health and disease - novel perspectives for translational research. (C) 2018 IBRO. Published by Elsevier Ltd. All rights reserved.