AMPK activation inhibits apoptosis and tau hyperphosphorylation mediated by palmitate in SH-SY5Y cells.

Obesity and diabetes have been shown to be associated with cognitive impairment or early neurodegeneration. However, the cellular mechanisms that link between these two pathologies have not been clarified. In this study, we treated SH-SY5Y human neuroblastoma cells with palmitate and observed its effect on cell apoptosis and tau hyperphosphorylation. Dose- and time-dependent effects of palmitate on apoptosis were observed. Palmitate treatment induced endoplasmic reticulum (ER) stress, determined by the expression of spliced X-box binding protein 1 (XBP-1) mRNA and immunoglobin heavy chain-binding protein (BiP). We also observed increases in c-Jun N-terminal kinase (JNK) activation and tau hyperphosphorylation in response to palmitate. Although palmitate did not impair insulin signaling as shown by the immunoblotting analysis of AKT phosphorylation, it did inactivate AMP-activated protein kinase (AMPK). Activation of AMPK by N(1)-(β-d-Ribofuranosyl)-5-aminoimidazole-4-carboxamide (AICAR), significantly reduced the apoptosis of cells treated with palmitate. AICAR also significantly inhibited ER stress, resulting in reduced tau hyperphosphorylation in cells treated with palmitate. Similarly, A769662, a direct activator of AMPK, also abolished the ER stress-mediated apoptosis and tau hyperphosphorylation. Therefore, these data suggest that palmitate triggers ER stress-mediated lipotoxicity and that AMPK activation inhibits apoptosis and tau hyperphosphorylation mediated by palmitate in SH-SY5Y cells.