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Science 314 (5799): 664-666

Copyright © 2006 by the American Association for the Advancement of Science

Control of Peripheral Nerve Myelination by the ß-Secretase BACE1

Michael Willem,1 Alistair N. Garratt,2* Bozidar Novak,1 Martin Citron,3 Steve Kaufmann,4 Andrea Rittger,5 Bart DeStrooper,6 Paul Saftig,5 Carmen Birchmeier,2 Christian Haass1*

Abstract: Although BACE1 (beta-site amyloid precursor protein–cleaving enzyme 1) is essential for the generation of amyloid-b peptide in Alzheimer's disease, its physiological function is unclear. We found that very high levels of BACE1 were expressed at time points when peripheral nerves become myelinated. Deficiency of BACE1 resulted in the accumulation of unprocessed neuregulin 1 (NRG1), an axonally expressed factor required for glial cell development and myelination. BACE1–/– mice displayed hypomyelination of peripheral nerves and aberrant axonal segregation of small-diameter afferent fibers, very similar to that seen in mice with mutations in type III NRG1 or Schwann cell–specific ErbB2 knockouts. Thus, BACE1 is required for myelination and correct bundling of axons by Schwann cells, probably through processing of type III NRG1.

1 Adolf Butenandt-Institute, Department of Biochemistry, Laboratory for Alzheimer's and Parkinson's Disease Research, Schillerstrasse 44, Ludwig-Maximilians-University, 80336 Munich, Germany.
2 Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strabe 10, 13092 Berlin, Germany.
3 Amgen Inc., Department of Neuroscience, Thousand Oaks, CA 93120, USA.
4 Amgen Inc., Department of Pathology, Thousand Oaks, CA 93120, USA.
5 Biochemical Institute, University of Kiel, Olshausenstrasse 40, 24098 Kiel, Germany.
6 Center for Human Genetics, K. U. Leuven and VIB, Department of Human Genetics, Herestraat 49, 3000 Leuven, Belgium.

* To whom correspondence should be addressed. E-mail: chaass{at} (C.H.); agarratt{at} (A.N.G.)

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Nucleic Acids Res. 35, 2975-2985
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Regulated Intramembrane Proteolysis of the Interleukin-1 Receptor II by {alpha}-, beta-, and {gamma}-Secretase.
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