Prestimulation of Microglia Through TLR4 Pathway Promotes Interferon Beta Expression in a Rat Model of Alzheimer's Disease.

Soluble amyloid beta (Aß) oligomers are the most common forms of Aß 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-ß) 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 Aß oligomer. After 24 h, cell pellets were harvested and TIR-domain-containing adapter-inducing interferon-ß (TRIF), interferon regulatory factor 3 (IRF3), and IFN-ß 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 Aß/vehicle was implanted in the left ventricle. After 2 weeks, TRIF, IRF3, and IFN-ß levels were measured in the hippocampal tissue. TNF-α and IFN-ß levels were assessed in the hippocampus using immunohistochemistry. The oligomeric Aß did not change TRIF, IRF3, and IFN-ß 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 Aß oligomer (10 µM). Pretreatment with LPS or MPL decreased the TNF-α and increased the number of IFN-ß positive cells in the hippocampus of Aß-treated rats. In conclusion, pretreatment with low dose TLR4 agonists could induce microglia to produce neuroprotective cytokines including IFN-ß which may be considered as a potential strategy to combat neuronal degeneration in AD.

Triggering microglia through toll-like receptor 2 pathway induced interferon ß expression in cell and animal model of Alzheimer's disease.

Synaptic function and memory performance are disrupted by soluble form of ß-amyloid (Aß). In the previous study, we found that early activation of microglia by toll-like receptor 2 (TLR2) attenuated Alzheimer's disease-associated cognitive deficit. This study was designed to investigate whether pretreatment with the TLR2 receptor ligand can regulate microglia to produce interferon ß (INFß) in a rat model of Alzheimer's disease. For this purpose, the BV-2 cell line was cultured in a 24-well plate, treated with Pam3Cys (1 µg/ml), and then incubated with oligomeric Aß for 24 h. The expression of TRIF, IRF3, and INFß was measured by western blot technique. For in-vivo study, bilateral guide cannulas were streotaxically implanted in the right and left lateral ventricles. Pam3Cys/vehicle was microinjected into the right ventricle every 3 days. Two weeks later, an osmotic pump was inserted into the left ventricle to microinfuse oligomeric Aß/placebo over 14 days. In the meanwhile, treatment with Pam3Cys was continued every 3 days. Then, expression of TRIF, IRF3, and INFß was measured in the hippocampus. The results showed that although oligomeric Aß could not alter the expression of these proteins at the cell and tissue level, treatment with Pam3Cys resulted in enhanced expression of them at both cell culture and hippocampal tissue following treatment with oligomeric Aß. It is concluded that stimulation of microglia through TLR2 pathway induces INFß expression, which may in part mediate neuroprotection against oligomeric Aß.