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Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid β-peptide

Nature Cell Biology volume 3, pages 905–912 (2001)Cite this article

Abstract

The pathogenic event common to all forms of Alzheimer's disease is the abnormal accumulation of the amyloid β-peptide (Aβ). Here we provide strong evidence that intracellular cholesterol compartmentation modulates the generation of Aβ. Using genetic, biochemical and metabolic approaches, we found that cholesteryl-ester levels are directly correlated with Aβ production. Acyl-coenzyme A:cholesterol acyltransferase (ACAT), the enzyme that catalyses the formation of cholesteryl esters, modulates the generation of Aβ through the tight control of the equilibrium between free cholesterol and cholesteryl esters. We also show that pharmacological inhibitors of ACAT, developed for the treatment of atherosclerosis, are potent modulators of Aβ generation, indicating their potential for use in the treatment of Alzheimer's disease.

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Figure 1: Lack of ACAT activity in AC29 cells elevates FC concentration in the ER membrane.
Figure 2: Cholesterol compartmentation regulates both APP processing and Aβ generation.
Figure 3: ACAT inhibitors alter cholesterol compartmentation and decrease Aβ generation in wild-type CHO cells.
Figure 4: The ACAT inhibitor CP113,818 normalizes CE and Aβ generation in 25RA cells.
Figure 5: Sterol deprivation normalizes both CE levels and Aβ secretion in 25RA cells.
Figure 6: The ACAT inhibitor CP113,818 regulates APP processing and Aβ generation in neuronal cell lines and primary neurons.
Figure 7: The ACAT inhibitor CP113,818 regulates the γ-secretase cleavage of APP and the steady-state levels of PS1 holoprotein and PS1 fragments.

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Acknowledgements

We thank C. C. Y. Chang and J. C. Cruz (Dartmouth Medical School, Hanover, New Hampshire) for the gift of cholesterol-mutant cells and competitive inhibitors of ACAT; A. J. Saunders for the CHO cells stably expressing BACE; and K. M. Lentini for her technical support. This work was supported by the American Health Assistance Foundation and the Neurosciences Education and Research Foundation (D.M.K.).

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Authors and Affiliations

  1. Genetics and Aging Research Unit, Massachusetts General Hospital, Harvard Medical School, Building 114, 16th Street, Charlestown, 02129-4404, Massachusetts, USA

    Luigi Puglielli, Eunju Pack-Chung, Laura A. MacKenzie Ingano, Rudolph E. Tanzi & Dora M. Kovacs

  2. Department of Neurology, Alzheimer Research Unit, Massachusetts General Hospital, Harvard Medical School, Building 114, 16th Street, Charlestown, 02129-4404, Massachusetts, USA

    Oksana Berezovska & Bradley T. Hyman

  3. Program in Neuroscience, Harvard Medical School, 200 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Genevieve Konopka

  4. Department of Biochemistry, Dartmouth Medical School, Hanover, 03755, New Hampshire, USA

    Ta Yuan Chang

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Puglielli, L., Konopka, G., Pack-Chung, E. et al. Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid β-peptide. Nat Cell Biol 3, 905–912 (2001). https://doi.org/10.1038/ncb1001-905

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