Secretory phospholipase A2 type III enhances α-secretase-dependent amyloid precursor protein processing through alterations in membrane fluidity

Abstract

In the non-amyloidogenic pathway, amyloid precursor protein (APP) is cleaved by α-secretases to produce α-secretase-cleaved soluble APP (sAPPα) with neuroprotective and neurotrophic properties; therefore, enhancing the non-amyloidogenic pathway has been suggested as a potential pharmacological approach for the treatment of Alzheimer's disease. Here, we demonstrate the effects of type III secretory phospholipase A2 (sPLA2-III) on sAPPα secretion. Exposing differentiated neuronal cells (SH-SY5Y cells and primary rat neurons) to sPLA2-III for 24 h increased sAPPα secretion and decreased levels of Aβ1−42 in SH-SY5Y cells, and these changes were accompanied by increased membrane fluidity. We further tested whether sPLA2-III-enhanced sAPPα release is due in part to the production of its hydrolyzed products, including arachidonic acid (AA), palmitic acid (PA), and lysophosphatidylcholine (LPC). Addition of AA but neither PA nor LPC mimicked sPLA2-III-induced increases in sAPPα secretion and membrane fluidity. Treatment with sPLA2-III and AA increased accumulation of APP at the cell surface but did not alter total expressions of APP, α-secretases, and β-site APP cleaving enzyme. Taken together, these results support the hypothesis that sPLA2-III enhances sAPPα secretion through its action to increase membrane fluidity and recruitment of APP at the cell surface.

Keywords

• arachidonic acid
• amyloid-β peptide
• Alzheimer's disease