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J. Biol. Chem., Vol. 282, Issue 36, 26326-26334, September 7, 2007

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Partial Reduction of BACE1 Has Dramatic Effects on Alzheimer Plaque and Synaptic Pathology in APP Transgenic Mice^*

Lisa McConlogue¹, Manuel Buttini², John P. Anderson, Elizabeth F. Brigham, Karen S. Chen³, Stephen B. Freedman⁴, Dora Games, Kelly Johnson-Wood, Michael Lee, Michelle Zeller, Weiqun Liu, Ruth Motter, and Sukanto Sinha²⁵

From the Departments of Biology and Pharmacology, Elan Pharmaceuticals, South San Francisco, California 94080

The aspartyl protease -site amyloid precursor protein cleaving enzyme 1 (BACE1) initiates processing of amyloid precursor protein (APP) into amyloid (A) peptide, the major component of Alzheimer disease (AD) plaques. To determine the role that BACE1 plays in the development of A-driven AD-like pathology, we have crossed PDAPP mice, a transgenic mouse model of AD overexpressing human mutated APP, onto mice with either a homozygous or heterozygous BACE1 gene knockout. Analysis of PDAPP/BACE(-/-) mice demonstrated that BACE1 is absolutely required for both A generation and the development of age-associated plaque pathology. Furthermore, synaptic deficits, a neurodegenerative pathology characteristic of AD, were also reversed in the bigenic mice. To determine the extent of BACE1 reduction required to significantly inhibit pathology, PDAPP mice having a heterozygous BACE1 gene knock-out were evaluated for A generation and for the development of pathology. Although the 50% reduction in BACE1 enzyme levels caused only a 12% decrease in A levels in young mice, it nonetheless resulted in a dramatic reduction in A plaques, neuritic burden, and synaptic deficits in older mice. Quantitative analyses indicate that brain A levels in young APP transgenic mice are not the sole determinant for the changes in plaque pathology mediated by reduced BACE1. These observations demonstrate that partial reductions of BACE1 enzyme activity and concomitant A levels lead to dramatic inhibition of A-driven AD-like pathology, making BACE1 an excellent target for therapeutic intervention in AD.

Received for publication, December 21, 2006 , and in revised form, June 29, 2007.

^* 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 Figs. 1 and 2.

² These authors contributed equally to the work.

³ Current address: Department of Neurosciences, Roche Palo Alto LLC, Palo Alto, CA 94304.

⁴ Current address: SBF Consulting, LLC, 355 First Street, #2301, San Francisco, CA 94105.

⁵ Current address: ActiveSite Pharmaceuticals, Inc., San Francisco, CA 94116.

¹ To whom correspondence should be addressed: Elan Pharmaceuticals, 800 Gateway Blvd., South San Francisco, CA 94010. Tel.: 650-877-7617; Fax: 650-866-2835; E-mail: lisa.mcconlogue{at}elan.com.

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