Activation of PPARδ suppresses BACE1 expression by upregulating SOCS1 in a JAK2/STAT1-dependent manner.

Neuronal expression of beta-secretase 1 (BACE1) has been implicated in the progression of Alzheimer's disease. However, the mechanisms that regulate BACE1 expression are unclear. Here, we show that peroxisome proliferator-activated receptor delta (PPAR delta) decreases BACE1 expression by up-regulating suppressor of cytokine signaling 1 (SOCS1) in SH-SY5Y neuroblastoma cells. The activation of PPAR delta by GW501516, a specific PPAR delta agonist, inhibited expression of BACE1. This effect was abrogated by shRNA-mediated knockdown of PPAR delta and by treatment with the PPAR delta antagonist GSK0660, indicating that PPAR delta is involved in GW501516-mediated suppression of BACE1 expression. On the other hand, GW501516-activated PPAR delta induced expression of SOCS1, which is a negative regulator of cytokine signal transduction, at the transcriptional level by binding to a PPAR response element in its promoter. This GW501516-mediated induction of SOCS1 expression led to down-regulation of BACE1 expression via inactivation of signal transducer and activator of transcription 1. GW501516-activated PPAR delta suppressed the generation of neurotoxic amyloid beta (A beta) in accordance with the decrease in BACE1 expression. Taken together, these results indicate that PPAR delta attenuates BACE1 expression via SOCS1-mediated inhibition of signal transducer and activator of transcription 1 signaling, thereby suppressing BACE1-associated generation of neurotoxic A beta.