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- Title
Activation of peroxisome proliferator‐activated receptor delta suppresses BACE1 expression by up‐regulating SOCS1 in a JAK2/STAT1‐dependent manner.
- Authors
Lee, Won Jin; Ham, Sun Ah; Lee, Gyeong Hee; Choi, Mi‐Jung; Yoo, Hyunjin; Paek, Kyung Shin; Lim, Dae‐Seog; Hong, Kwonho; Hwang, Jung Seok; Seo, Han Geuk
- Abstract
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 (PPARδ) decreases BACE1 expression by up‐regulating suppressor of cytokine signaling 1 (SOCS1) in SH‐SY5Y neuroblastoma cells. The activation of PPARδ by GW501516, a specific PPARδ agonist, inhibited expression of BACE1. This effect was abrogated by shRNA‐mediated knockdown of PPARδ and by treatment with the PPARδ antagonist GSK0660, indicating that PPARδ is involved in GW501516‐mediated suppression of BACE1 expression. On the other hand, GW501516‐activated PPARδ 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 PPARδ suppressed the generation of neurotoxic amyloid beta (Aβ) in accordance with the decrease in BACE1 expression. Taken together, these results indicate that PPARδ attenuates BACE1 expression via SOCS1‐mediated inhibition of signal transducer and activator of transcription 1 signaling, thereby suppressing BACE1‐associated generation of neurotoxic Aβ.
- Subjects
NUCLEAR receptors (Biochemistry); PEROXISOME proliferator-activated receptors; MICROPHTHALMIA-associated transcription factor; ALZHEIMER'S disease; CELLULAR signal transduction
- Publication
Journal of Neurochemistry, 2019, Vol 151, Issue 3, p370
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1111/jnc.14715