Activation of peroxisome proliferator‐activated receptor delta suppresses BACE 1 expression by up‐regulating SOCS 1 in a JAK 2/ STAT 1‐dependent manner

Neuronal expression of beta‐secretase 1 ( BACE 1) has been implicated in the progression of Alzheimer's disease. However, the mechanisms that regulate BACE 1 expression are unclear. Here, we show that peroxisome proliferator‐activated receptor delta ( PPAR δ) decreases BACE 1 expression by up‐regulating suppressor of cytokine signaling 1 ( SOCS 1) in SH ‐ SY 5Y neuroblastoma cells. The activation of PPAR δ by GW 501516, a specific PPAR δ agonist, inhibited expression of BACE 1. This effect was abrogated by sh RNA ‐mediated knockdown of PPAR δ and by treatment with the PPAR δ antagonist GSK 0660, indicating that PPAR δ is involved in GW 501516‐mediated suppression of BACE 1 expression. On the other hand, GW 501516‐activated PPAR δ induced expression of SOCS 1, which is a negative regulator of cytokine signal transduction, at the transcriptional level by binding to a PPAR response element in its promoter. This GW 501516‐mediated induction of SOCS 1 expression led to down‐regulation of BACE 1 expression via inactivation of signal transducer and activator of transcription 1. GW 501516‐activated PPAR δ suppressed the generation of neurotoxic amyloid beta (Aβ) in accordance with the decrease in BACE 1 expression. Taken together, these results indicate that PPAR δ attenuates BACE 1 expression via SOCS 1‐mediated inhibition of signal transducer and activator of transcription 1 signaling, thereby suppressing BACE 1‐associated generation of neurotoxic Aβ.