TRAIL-R Deficient Mice Are Protected from Neurotoxic Effects of Amyloid-beta

TRAIL, a member of TNF superfamily, is a potent inducer of neuronal death. Neurotoxic effects of TRAIL appear mediated by its death receptor TRAIL-R2/DR5. To assess the role of TRAIL/TRAIL-R2 pathway in AD-related neurodegeneration, we studied the impact of the treatment with amyloid-beta (A beta) upon cell viability and inflammation in TRAIL-R-deficient mice (TRAIL-R-/-). Here, we demonstrate that the lack of TRAIL-R2 protects from death cultured TRAIL-R-/- mouse embryonic hippocampal cells after treatment with either A beta 1-42 or TRAIL. Consistently, stereotaxic injection of A beta 1-42 resulted in blunted caspase activation, as well as in reduction of JNK phosphorylation and increased AKT phosphorylation in TRAIL-R-/- mice. Moreover, the lack of TRAIL-R2 was associated with blunted constitutive p53 expression in mice that have undergone A beta 1-42 treatment, as well as in decrease of phosphorylated forms of tau and GSK3 beta proteins. Likewise, TRAIL-R2 appears essential to both TRAIL and A beta-mediated neurotoxicity and inflammation. Indeed, hippocampi of TRAIL-R-/- mice challenged with A beta 1-42, showed a slight expression of microglial (Iba-1) and astrocytic (GFAP) markers along with attenuated levels of IL-1 beta, TNF-alpha, NOS2 and COX2. In conclusion, the bulk of these results demonstrate that the constitutive lack of TRAIL-R2 is associated with a substantial reduction of noxious effects of A beta 1-42, providing further evidence on the prominent role played by TRAIL in course of A beta-related neurodegeneration and confirming that the TRAIL system represents a potential target for innovative AD therapy.