International Journal of Alzheimer's Disease
Volume 2011 (2011), Article ID 695413, 8 pages
doi:10.4061/2011/695413
Research Article

Intracellular APP Domain Regulates Serine-Palmitoyl-CoA Transferase Expression and Is Affected in Alzheimer's Disease

Marcus O. W. Grimm,1 Sven Grösgen,1 Tatjana L. Rothhaar,1 Verena K. Burg,1 Benjamin Hundsdörfer,1 Viola J. Haupenthal,1 Petra Friess,1 Ulrike Müller,2 Klaus Fassbender,1,3 Matthias Riemenschneider,1,4 Heike S. Grimm,1 and Tobias Hartmann1,4

1Neurodegeneration and Neurobiology, Deutsches Institut für Demenzprävention (DIDP), Kirrbergerstraße, 66421 Homburg, Germany
2Institute of Pharmacy and Molecular Biotechnology (IPMB), University of Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany
3Department of Neurology, Saarland University, Kirrbergerstraße, 66421 Homburg/Saar, Germany
4Department of Psychiatry, Saarland University, Kirrbergerstraße, 66421 Homburg/Saar, Germany

Received 15 October 2010; Revised 16 January 2011; Accepted 20 January 2011

Academic Editor: Katsuhiko Yanagisawa

Copyright © 2011 Marcus O. W. Grimm 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), a disease biochemically characterized by the accumulation of amyloid beta peptides (Aβ), released by proteolytic processing of the amyloid precursor protein (APP). Changes in sphingolipid metabolism have been associated to the development of AD. The key enzyme in sphingolipid de novo synthesis is serine-palmitoyl-CoA transferase (SPT). In the present study we identified a new physiological function of APP in sphingolipid synthesis. The APP intracellular domain (AICD) was found to decrease the expression of the SPT subunit SPTLC2, the catalytic subunit of the SPT heterodimer, resulting in that decreased SPT activity. AICD function was dependent on Fe65 and SPTLC2 levels are increased in APP knock-in mice missing a functional AICD domain. SPTLC2 levels are also increased in familial and sporadic AD postmortem brains, suggesting that SPT is involved in AD pathology.