Effect of Different Phospholipids on α-Secretase Activity in the Non-Amyloidogenic Pathway of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by extracellular accumulation of amyloid-beta peptide (A beta), generated by proteolytic processing of the amyloid precursor protein (APP) by beta- and gamma-secretase. A beta generation is inhibited when the initial ectodomain shedding is caused by alpha-secretase, cleaving APP within the A beta domain. Therefore, an increase in alpha-secretase activity is an attractive therapeutic target for AD treatment. APP and the APP-cleaving secretases are all transmembrane proteins, thus local membrane lipid composition is proposed to influence APP processing. Although several studies have focused on gamma-secretase, the effect of the membrane lipid microenvironment on alpha-secretase is poorly understood. In the present study, we systematically investigated the effect of fatty acid (FA) acyl chain length (10:0, 12:0, 14:0, 16:0, 18:0, 20:0, 22:0, 24:0), membrane polar lipid headgroup (phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine), saturation grade and the FA double-bond position on alpha-secretase activity. We found that alpha-secretase activity is significantly elevated in the presence of FAs with short chain length and in the presence of polyunsaturated FAs, whereas variations in the phospholipid headgroups, as well as the double-bond position, have little or no effect on alpha-secretase activity. Overall, our study shows that local lipid membrane composition can influence alpha-secretase activity and might have beneficial effects for AD.