Suppression Of LPS-induced Tau Hyperphosphorylation By Serum Amyloid A

Background:Accumulation of hyperphosphorylated tau is a major neuropathological feature of tauopathies including Alzheimer's disease(AD).Serum amyloid A(SAA),an acute-phase protein with cytokine-like property,has been implicated in amyloid deposition.It remains unclear whether SAA affects tauhyperphosphorylationMethods:Potential involvement of SAA in tau hyperphosphorylation was examined using intracerebral injection of SAA,and in Saa3-/-,Saa3-Tg mice receiving systemic administration of LPS.SAA expression and microglial activation were evaluated in these mice using real-time PCR and/or immunofluorecence staining Cultured primary neuronal cells were treated with condition media(CM)from SAA-stimulated primary microglial cells.The alteration in tau hyperphosphorylation was determined using Western blottingResults:SAA3 is the predominant form of SAA proteins induced by LPS in mouse brain,which co-localizes with neurons.Over-expression of SAA by intracerebral injection attenuated tau hyperphosphorylation in the brain.Saa3 deficiency enhanced tau phosphorylation after systemic LPS administration Conversely,the effect of LPS was attenuated in Saa3-Tg mice.Intracerebral injection of SAA also induced the activation of microglia in the brains.IL-10 released by CM from SAA-stimulated microglia attenuated tau hyperphosphorylation in cultured primary neurons.IL-10 neutralizing antibody reversed the decrease of tau phosphorylation induced by SAA intracerebral injectionConclusions:LPS-induced expression of SAA proteins in the brain leads to activation of microglia and release of IL-10,which in turn suppresses tau hyperphosphorylation in a mouse model of systemic inflammation.