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The Scientific World Journal
Volume 2012, Article ID 141240, 15 pages
http://dx.doi.org/10.1100/2012/141240
Research Article

Plasmalogens Inhibit APP Processing by Directly Affecting γ-Secretase Activity in Alzheimer’s Disease

1Experimental Neurology, Saarland University, Kirrbergerstraβe, 66421 Homburg/Saar, Germany
2Psychiatry, Saarland University, Kirrbergerstraβe, 66421 Homburg/Saar, Germany
3Deutsches Institut für DemenzPrävention (DIDP), Universität des Saarlandes, Kirrbergerstraβe, 66421 Homburg/Saar, Germany
4Neurodegeneration and Neurobiology, Saarland University, Kirrbergerstraβe, 66421 Homburg/Saar, Germany

Received 10 October 2011; Accepted 30 November 2011

Academic Editor: Dietmar R. Thal

Copyright © 2012 Tatjana L. Rothhaar et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Lipids play an important role as risk or protective factors in Alzheimer’s disease (AD). Previously it has been shown that plasmalogens, the major brain phospholipids, are altered in AD. However, it remained unclear whether plasmalogens themselves are able to modulate amyloid precursor protein (APP) processing or if the reduced plasmalogen level is a consequence of AD. Here we identify the plasmalogens which are altered in human AD postmortem brains and investigate their impact on APP processing resulting in Aβ production. All tested plasmalogen species showed a reduction in γ-secretase activity whereas β- and α-secretase activity mainly remained unchanged. Plasmalogens directly affected γ-secretase activity, protein and RNA level of the secretases were unaffected, pointing towards a direct influence of plasmalogens on γ-secretase activity. Plasmalogens were also able to decrease γ-secretase activity in human postmortem AD brains emphasizing the impact of plasmalogens in AD. In summary our findings show that decreased plasmalogen levels are not only a consequence of AD but that plasmalogens also decrease APP processing by directly affecting γ-secretase activity, resulting in a vicious cycle: Aβ reduces plasmalogen levels and reduced plasmalogen levels directly increase γ-secretase activity leading to an even stronger production of Aβ peptides.