Abstract
Soluble amyloid beta (Aβ) oligomers are the most common forms of Aβ in the early stage of Alzheimer’s disease (AD). They are highly toxic to the neurons but their capability to activate microglia remains controversial. Microglia develop two distinct phenotypes, classic (M1) and alternative (M2). Tuning of microglia to the alternative (anti-inflammatory) state is of major interest in treatment of neuroinflammatory disease. This study aimed to assess tuning the microglia to produce interferon beta (IFN-β) as an anti-inflammatory cytokine through TLR4 pathway in a rat model of AD. Microglial BV-2 cells were treated with 1 μg/ml lipopolysaccharides (LPS), Monophosphoryl lipid A (MPL), or vehicles for 24 h, and then incubated with Aβ oligomer. After 24 h, cell pellets were harvested and TIR-domain-containing adapter-inducing interferon-β (TRIF), interferon regulatory factor 3 (IRF3), and IFN-β levels were measured. The ligands/vehicle were microinjected into the right ventricle of male Wistar rats every 3 days. Two weeks later, an osmotic pump filled with oligomeric Aβ/vehicle was implanted in the left ventricle. After 2 weeks, TRIF, IRF3, and IFN-β levels were measured in the hippocampal tissue. TNF-α and IFN-β levels were assessed in the hippocampus using immunohistochemistry. The oligomeric Aβ did not change TRIF, IRF3, and IFN-β levels in both cell culture and hippocampal tissue. However, pretreatment with LPS or MPL increased the level of these proteins. BV-2 cells morphologically express M1 state in presence of higher dose of Aβ oligomer (10 μM). Pretreatment with LPS or MPL decreased the TNF-α and increased the number of IFN-β positive cells in the hippocampus of Aβ-treated rats. In conclusion, pretreatment with low dose TLR4 agonists could induce microglia to produce neuroprotective cytokines including IFN-β which may be considered as a potential strategy to combat neuronal degeneration in AD.
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Yousefi, N., Sotoodehnejadnematalahi, F., Heshmati-Fakhr, N. et al. Prestimulation of Microglia Through TLR4 Pathway Promotes Interferon Beta Expression in a Rat Model of Alzheimer’s Disease. J Mol Neurosci 67, 495–503 (2019). https://doi.org/10.1007/s12031-018-1249-1
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DOI: https://doi.org/10.1007/s12031-018-1249-1