期刊
NEUROBIOLOGY OF AGING
卷 40, 期 -, 页码 181-190出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2016.01.132
关键词
PPAR gamma; PGC1 alpha; hNSCs; A beta
资金
- Ministry of Science and Technology [MOST 103-2320-B-030-006]
- Fu Jen Catholic University [A0203104, A0204104, A0104020]
- Terry Whole Brain & Potential Development Center [Terry 104-11-01]
Neuronal cell impairment, such as that induced by amyloid-beta (A beta) protein, is a process with limited therapeutic interventions and often leads to long-term neurodegeneration common in disorders such as Alzheimer's disease. Interestingly, peroxisome proliferator-activated receptor gamma (PPAR gamma) is a ligand-activated nuclear receptor whose ligands control many physiological and pathologic processes, and may be neuroprotective. We hypothesized that rosiglitazone, a PPAR gamma agonist, would prevent A beta-mediated effects in human neural stem cells (hNSCs). Here, we show that rosiglitazone reverses, via PPAR gamma-dependent downregulation of caspase 3 and 9 activity, the A beta-mediated decreases in hNSC cell viability. In addition, A beta decreases hNSC messenger RNA (mRNA) levels of 2 neuroprotective factors (Bcl-2 and CREB), but co-treatment with rosiglitazone significantly rescues these effects. Rosiglitazone co-treated hNSCs also showed significantly increased mitochondrial function (reflected by levels of adenosine triphosphate and Mit mass), and PPAR gamma-dependent mRNA upregulation of PGC1 alpha and mitochondrial genes (nuclear respiratory factor-1 and Tfam). Furthermore, hNSCs co-treated with rosiglitazone were significantly rescued from A beta-induced oxidative stress and correlates with reversal of the A beta-induced mRNA decrease in oxidative defense genes (superoxide dismutase 1, superoxide dismutase 2, and glutathione peroxidase 1). Taken together, these novel findings show that rosiglitazone-induced activation of PPAR gamma-dependent signaling rescues A beta-mediated toxicity in hNSCs and provide evidence supporting a neuroprotective role for PPAR gamma activating drugs in A beta-related diseases such as Alzheimer's disease. (C) 2016 Elsevier Inc. All rights reserved.
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