Early minor stimulation of microglial TLR2 and TLR4 receptors attenuates Alzheimer's disease-related cognitive deficit in rats: behavioral, molecular, and electrophysiological evidence

At early stages of Alzheimer's disease (AD), soluble amyloid beta (A beta) accumulates in brain while microglia are in resting state. Microglia can recognize A beta long after formation of plaques and release neurotoxic mediators. We examined impact of early minor activation of microglia by Toll-like receptors (TLRs) 2 and 4 agonists on Alzheimer's disease-related disturbed synaptic function and spatial memory in rats. Microglial BV-2 cells were treated by 0.1, 1, and 10 mg/mL of the TLRs ligands lipopolysaccharide, monophosphoryl lipid A (MPL), and Pam3Cys for 24 hours. Culture medium was then changed with media containing 1-mM A beta. Tumour necrosis factor (TNF)-alpha and CCL3 levels were measured in the supernatant, 24 hours thereafter. One mg of TLRs ligands which was able to release low level of TNF-alpha and CCL3, was administered intracerebroventricularly (i. c. v) to adult male rats every 3 days for 24 days. At the half of the treatment period, A beta 1-42 was infused i. c. v (0.075 mg/hour) for 2 weeks. Finally, the following factors were measured: memory performance by Morris water maze, postsynaptic potentials of dentate gyrus following perforant pathway stimulation, hippocampal inflammatory cytokines interleukin 1 (IL-1) b and TNF-alpha, anti-inflammatory cytokines IL-10 and TGF-1 beta, microglia marker arginase 1, A beta deposits, and the receptor involved in A beta clearance, formyl peptide receptor 2 (FPR2). TLRs ligands caused dosedependent release of TNF-alpha and CCL3 by BV-2 cells. A beta-treated cells did not release TNF-alpha and CCL3, whereas those pretreated with MPL and Pam3Cys significantly released these cytokines in response to A beta. Low-dose TLRs ligands improved the disturbance in spatial and working memory; restored the impaired long-term potentiation induced by A beta; decreased TNF-alpha, and A beta deposits; enhanced TGF-1 beta, IL10, and arginase 1 in the hippocampus of A beta-treated rats; and increased polarization of hippocampal microglia to the anti-inflammatory phenotype. The ligands increased formyl peptide receptor 2 in both BV-2 cells and hippocampus/cortex of A beta-treated rats. Microglia can sense/clear soluble A beta by early lowdose MPL and Pam3Cys and safeguard synaptic function and memory in rats. (C) 2018 Elsevier Inc. All rights reserved.