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J. Biol. Chem., Vol. 283, Issue 27, 18694-18701, July 4, 2008

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Promotion of BACE1 mRNA Alternative Splicing Reduces Amyloid β-Peptide Production^*

From the Center for Neurologic Diseases, Brigham Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115

Production of the amyloid β-peptide (Aβ) via sequential proteolytic cleavage of the amyloid precursor protein by β- and -secretases is strongly implicated in the pathogenesis of Alzheimer disease. The β-secretase that executes the first cleavage event is a transmembrane aspartyl protease known as β-site amyloid precursor protein-cleaving enzyme 1 (BACE1). BACE1 pre-mRNA is alternatively spliced through the use of alternative splice sites in exons 3 and 4, although the significance of these splicing events is unclear. Here, we quantitatively measured relative levels of BACE1 transcripts and identified a novel splice variant of BACE1. We found a subtle but significant difference in BACE1 splicing between brain and pancreas, indicating the cellular environment can affect BACE1 alternative splicing. Furthermore, we have shown that BACE1 proteins translated from alternatively spliced transcripts have dramatically reduced β-secretase activity and promotion of BACE1 alternative splicing reduces Aβ production. These findings illustrate the importance of BACE1 alternative splicing in affecting the level of Aβ produced in cells and suggest that targeting regulation of BACE1 alternative splicing is a potential therapeutic strategy for lowering β-secretase activity.

Received for publication, February 19, 2008 , and in revised form, May 6, 2008.

^* This work was supported by the Foundation for Neurologic Diseases. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed: 77 Ave. Louis Pasteur, HIM 754, Boston, MA 02115. E-mail: mwolfe{at}rics.bwh.harvard.edu.

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