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15-Deoxy-⌬12,14 -prostaglandin J 2 (15-deoxy-PGJ 2 ), a naturally occurring ligand, activates the peroxisome proliferator-activated receptor-␥ (PPAR-␥). Activation of PPAR-␥ has been found to induce cell differentiation in such cells as adipose cells and macrophages. Herein, we investigated whether 15-deoxy-PGJ 2 has neuronal cell differentiation and possible underlying molecular mechanisms. Dopaminergic differentiating PC-12 cells treated with 15-deoxy-PGJ 2 (0.2 to 1.6 M) alone showed measurable neurite extension and expression of neurofilament, a marker of cell differentiation. However, a much greater extent of neurite extension and expression of neurofilament was observed in the presence of NGF (50 ng/ml). In parallel with its increasing effect on the neurite extension and expression of neurofilament, 15-deoxy-PGJ 2 enhanced NGF-induced p38 MAP kinase expression and its phosphorylation in addition to the activation of transcription factor AP-1 in a dose-dependent manner. Moreover, pretreatment of 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(pyridyl)1H-imidazole (SB203580), a specific inhibitor of p38 MAP kinase, inhibited the promoting effect of 15-deoxy-PGJ 2 (0.8 M) on NGF-induced neurite extension. This inhibition correlated well with the ability of SB203580 to inhibit the enhancing effect of 15-deoxy-PGJ 2 on the expression of p38 MAP kinase and activation of AP-1. The promoting ability of 15-deoxy-PGJ 2 did not occur through PPAR-␥ because synthetic PPAR-␥ agonist and antagonist did not change the neurite-promoting effect of 15-deoxy-PGJ 2 . In addition, contrast to other cells (embryonic midbrain and neuroblastoma SK-N-MC cells), PPAR-␥ was not expressed in PC-12 cells. Other structure-related prostaglandins (PGD 2 and PGE 2 ) acting via a cell surface G-protein-coupled receptor (GPCR) did not increase basal or NGF-induced neurite extension. Moreover, GPCR (PGE 2 and PGD 2 receptors) antagonists did not alter the promoting effect of 15-deoxy-PGJ 2 on neurite extension and activation of p38 MAP kinase, suggesting that the promoting effect of 15-deoxy-PGJ 2 may not be mediated by GPCR either. These data demonstrate that activation of p38

In its late stage, Alzheimer's disease results in progressive muscle weakness in the arms and legs. The aim of this study was to determine whether mice expressing the skeletal muscle-specific mutant PS2 gene (a model of Alzheimer's disease) are a useful experimental system to study the protective effect of exercise on A beta-42 reduction, improvement of behavioural function and changes in metabolic parameters. With this aim in mind, the transgenic mice were subjected to treadmill exercise for 3 months. The results showed that in transgenic mice, but not in normal mice, treadmill exercise resulted in a reduction of A beta-42 deposits and an improvement in behavioural function, thereby restoring normal concentrations of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglyceride. Thus, exercise may represent a practical therapeutic strategy for use with human patients with Alzheimer's disease.