Deficiency Of Macrophage Migration Inhibitory Factor Attenuates Tau Hyperphosphorylation In Mouse Models Of Alzheimer's Disease

Background: Pathological features of Alzheimer's disease(AD) include aggregation of amyloid beta(A?) and tau protein. Macrophage migration inhibitory factor(MIF), a proinflammatory cytokine, has been implicated in the toxicity of aggregated A?. It remains unclear whether MIF affects hyperphosphorylation and aggregation of tau protein.Methods: The effects of MIF deficiency in tau hyperphosphorylation were examined in Mif-/- mice receiving intracerebroventricular(ICV) injection of Streptozotocin(STZ) and in APP/PS1 transgenic mice mated with Mif-/- mice. MIF expression and astrocyte activation were evaluated in ICV-STZ mice using immunofluorecence staining. Cultured primary neuronal cells were treated with high glucose to mimic STZ function in vitro and the alteration in tau hyperphosphorylation was determined using Western blotting.Results: MIF deficiency attenuated tau hyperphosphorylation in the brains of these mouse models. ICV injection of STZ increased expression of MIF, which co-localized with activated astrocytes in the hippocampus. ICV-STZ also increased astrocyte activation in WT mice, and MIF deficiency attenuated astrocyte activation in ICV-STZ treated mice. Conditioned medium from high glucose-treated WT astrocytes increased tau hyperphosphorylation in cultured primary neurons, but this effect was absent in Mif-/- astrocytes. MIF or the small molecule MIF inhibitor ISO-1 showed no direct effect on tau phosphorylation in cultured primary neurons.Conclusions: These results suggest that genetic Mif deficiency is associated with reduced astrocyte activation and tau hyperphosphorylation in two mouse models of AD. Inhibition of MIF and MIF induced astrocyte activation may be valuable for AD prevention and therapy.