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J. Biol. Chem., Vol. 280, Issue 38, 32957-32967, September 23, 2005

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High -Secretase Activity Elicits Neurodegeneration in Transgenic Mice Despite Reductions in Amyloid- Levels

IMPLICATIONS FOR THE TREATMENT OF ALZHEIMER DISEASE^*

Edward Rockenstein, Michael Mante, Michael Alford, Anthony Adame, Leslie Crews, Makoto Hashimoto, Luke Esposito¶, Lennart Mucke¶, and Eliezer Masliah||1

From the Neurosciences and ^||Pathology, University of California, San Diego, School of Medicine, La Jolla, California 92093-0624 and the Gladstone Institute of Neurological Disease and ^¶Department of Neurology, University of California, San Francisco, California 94158

Amyloid- peptides (A) are widely presumed to play a causal role in Alzheimer disease. Release of A from the amyloid precursor protein (APP) requires proteolysis by the -site APP-cleaving enzyme (BACE1). Although increased BACE1 activity in Alzheimer disease brains and human (h) BACE1 transgenic (tg) mice results in altered APP cleavage, the contribution of these molecular alterations to neurodegeneration is unclear. We therefore used the murine Thy1 promoter to express high levels of hBACE1, with or without hAPP, in neurons of tg mice. Compared with hAPP mice, hBACE1/hAPP doubly tg mice had increased levels of APP C-terminal fragments (C89, C83) and decreased levels of full-length APP and A. In contrast to non-tg controls and hAPP mice, hBACE1 mice and hBACE1/hAPP mice showed degeneration of neurons in the neocortex and hippocampus and degradation of myelin. Neurological deficits were also more severe in hBACE1 and hBACE1/hAPP mice than in hAPP mice. These results demonstrate that high levels of BACE1 activity are sufficient to elicit neurodegeneration and neurological decline in vivo. This pathogenic pathway involves the accumulation of APP C-terminal fragments but does not depend on increased production of human A. Thus, inhibiting BACE1 may block not only A-dependent but also A-independent pathogenic mechanisms.

Received for publication, June 28, 2005 , and in revised form, July 13, 2005.

^* This work was supported by National Institutes of Health Grants AG18440, AG10869, AG5131, and AG022074. 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.

¹ To whom correspondence should be addressed: Dept. of Neurosciences, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0624. Tel.: 858-534-8992; Fax: 858-534-6232; E-mail: emasliah{at}ucsd.edu.

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