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Regulation of cholesterol and sphingomyelin metabolism by amyloid-β and presenilin

Nature Cell Biology volume 7, pages 1118–1123 (2005)Cite this article

A Corrigendum to this article was published on 01 April 2006

Abstract

Amyloid beta peptide (Aβ) has a key role in the pathological process of Alzheimer's disease (AD), but the physiological function of Aβ and of the amyloid precursor protein (APP) is unknown1,2. Recently, it was shown that APP processing is sensitive to cholesterol and other lipids3,4,5,6,7,8,9,10. Hydroxymethylglutaryl-CoA reductase (HMGR) and sphingomyelinases (SMases) are the main enzymes that regulate cholesterol biosynthesis and sphingomyelin (SM) levels, respectively. We show that control of cholesterol and SM metabolism involves APP processing. Aβ42 directly activates neutral SMase and downregulates SM levels, whereas Aβ40 reduces cholesterol de novo synthesis by inhibition of HMGR activity. This process strictly depends on γ-secretase activity. In line with altered Aβ40/42 generation, pathological presenilin mutations result in increased cholesterol and decreased SM levels. Our results demonstrate a biological function for APP processing and also a functional basis for the link that has been observed between lipids and Alzheimer's disease (AD).

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Figure 1: Presenilin in lipid homeostasis.
Figure 2: Aβ and APP function in lipid homeostasis.
Figure 3: Effects of PS-FAD mutations on cellular cholesterol, SM 18:0 levels and nSMase activity.
Figure 4: Model of γ-secretase activity in lipid homeostasis.

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Acknowledgements

We are grateful to I. Tomic and R. Stammann for excellent technical assistance; B. Penke for peptides; T. Ruppert for mass-spectrometry advice and support; and for funding received from the European Union via QLK-172-2002 Lipidiet, Deutsche Forschungsgemeinschaft and Bundesministerium für Bildung und Forschung.

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Authors and Affiliations

  1. Centre for Molecular Biology Heidelberg, INF 282, Heidelberg, D-69120, Germany

    Marcus O. W. Grimm, Heike S. Grimm, Andreas J. Pätzold, Eva G. Zinser, Riikka Halonen, Marco Duering, Jakob-A. Tschäpe & Tobias Hartmann

  2. Department of Human Genetics, VIB4 and KU Leuven, Leuven, B-3000, Belgium

    Bart De Strooper

  3. Institute for Pharmacy and Molecular Biotechnology, INF 364, Heidelberg, D-69120, Germany

    Ulrike Müller

  4. Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, MA, USA

    Jie Shen

  5. Max Planck Institute for Brain Research, Deutschordenstrassen 46,, Frankfurt, D-60528, Germany

    Ulrike Müller

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Correspondence to Tobias Hartmann.

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Supplementary figures S1, S2, S3 ,S4 and Supplementary Materials and Methods plus Supplementary References (PDF 104 kb)

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Grimm, M., Grimm, H., Pätzold, A. et al. Regulation of cholesterol and sphingomyelin metabolism by amyloid-β and presenilin. Nat Cell Biol 7, 1118–1123 (2005). https://doi.org/10.1038/ncb1313

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