is Induced by Aging and Neurodegeneration to Modulate Stress Signaling and Its Deficiency Exacerbates Tau-mediated Neurodegeneration

Toll-9 is most closely related to mammalian Toll-like receptors; however, physiological functions of Toll-9 remain elusive. We examined the roles of Toll-9 in fly brains in aging and neurodegeneration. mRNA levels were increased in aged fly heads accompanied by activation of nuclear factor-kappa B (NF-kB) and stress-activated protein kinase (SAPK) signaling, and many of these changes were modulated by in glial cells. The loss of did not affect lifespan or brain integrity, whereas it exacerbated hydrogen peroxide-induced lethality. expression was also induced by nerve injury but did not affect acute stress response or glial engulfment activity, suggesting may modulate subsequent neurodegeneration. In a fly tauopathy model, deficiency enhanced neurodegeneration and disease-related tau phosphorylation with reduced SAPK activity, and blocking SAPK enhanced tau phosphorylation and neurodegeneration. In sum, Toll-9 is induced upon aging and nerve injury and affects neurodegeneration by modulating stress kinase signaling.