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Effect of Different Phospholipids on α-Secretase Activity in the Non-Amyloidogenic Pathway of Alzheimer’s Disease
Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany
Neurodegeneration and Neurobiology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany
Deutsches Institut für DemenzPrävention (DIDP), Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany
These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 13 December 2012; in revised form: 19 January 2013 / Accepted: 1 March 2013 / Published: 13 March 2013
Abstract: Alzheimer’s disease (AD) is characterized by extracellular accumulation of amyloid-β peptide (Aβ), generated by proteolytic processing of the amyloid precursor protein (APP) by β- and γ-secretase. Aβ generation is inhibited when the initial ectodomain shedding is caused by α-secretase, cleaving APP within the Aβ domain. Therefore, an increase in α-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 γ-secretase, the effect of the membrane lipid microenvironment on α-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 α-secretase activity. We found that α-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 α-secretase activity. Overall, our study shows that local lipid membrane composition can influence α-secretase activity and might have beneficial effects for AD.
Keywords: Alzheimer’s disease; α-secretase; ADAM10; lipids; phospholipids; chain length; saturation; headgroup
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Grimm, M.O.W.; Haupenthal, V.J.; Rothhaar, T.L.; Zimmer, V.C.; Grösgen, S.; Hundsdörfer, B.; Lehmann, J.; Grimm, H.S.; Hartmann, T. Effect of Different Phospholipids on α-Secretase Activity in the Non-Amyloidogenic Pathway of Alzheimer’s Disease. Int. J. Mol. Sci. 2013, 14, 5879-5898.
Grimm MOW, Haupenthal VJ, Rothhaar TL, Zimmer VC, Grösgen S, Hundsdörfer B, Lehmann J, Grimm HS, Hartmann T. Effect of Different Phospholipids on α-Secretase Activity in the Non-Amyloidogenic Pathway of Alzheimer’s Disease. International Journal of Molecular Sciences. 2013; 14(3):5879-5898.
Grimm, Marcus O.W.; Haupenthal, Viola J.; Rothhaar, Tatjana L.; Zimmer, Valerie C.; Grösgen, Sven; Hundsdörfer, Benjamin; Lehmann, Johannes; Grimm, Heike S.; Hartmann, Tobias. 2013. "Effect of Different Phospholipids on α-Secretase Activity in the Non-Amyloidogenic Pathway of Alzheimer’s Disease." Int. J. Mol. Sci. 14, no. 3: 5879-5898.