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J. Biol. Chem., Vol. 281, Issue 5, 2405-2413, February 3, 2006

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Down-regulation of Endogenous Amyloid Precursor Protein Processing due to Cellular Aging^*

Andreas Kern, Birgit Roempp, Kai Prager, Jochen Walter, and Christian Behl¹

From the Institute for Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg University Mainz, 55099 Mainz, Germany and Department of Neurology, University of Bonn, 53121 Bonn, Germany

Processing of amyloid precursor protein (APP) is a well acknowledged central pathogenic mechanism in Alzheimer disease. However, influences of age-associated cellular alterations on the biochemistry of APP processing have not been studied in molecular detail so far. Here, we report that processing of endogenous APP is down-regulated during the aging of normal human fibroblasts (IMR-90). The generation of intracellular APP cleavage products C99, C83, and AICD gradually declines with increasing life span and is accompanied by a reduced secretion of soluble APP (sAPP) and sAPP. Further, the maturation of APP was reduced in senescent cells, which has been shown to be directly mediated by age-associated increased cellular cholesterol levels. Of the APP processing secretases, protein levels of constituents of the -secretase complex, presenilin-1 (PS1) and nicastrin, were progressively reduced during aging, resulting in a progressive decrease in -secretase enzymatic activity. ADAM10 (a disintegrin and metalloprotease 10) and BACE (-site APP-cleaving enzyme) protein levels exhibited no age-associated regulation, but interestingly, BACE enzymatic activity was increased in aged cells. PS1 and BACE are located in detergent-resistant membranes (DRMs), well structured membrane microdomains exhibiting high levels of cholesterol, and caveolin-1. Although total levels of both structural components of DRMs were up-regulated in aged cells, their particular DRM association was decreased. This age-dependent membrane modification was associated with an altered distribution of PS1 and BACE between DRM and non-DRM fractions, very likely affecting their APP processing potential. In conclusion, we have found a significant modulation of endogenous APP processing and maturation in human fibroblasts caused by age-associated alterations in cellular biochemistry.

Received for publication, May 23, 2005 , and in revised form, October 19, 2005.

^* This work was supported by grants from the Deutsche Alzheimer Stiftung and the Fritz und Hildegard Berg-Stiftung (to C. B.) and a grant of the Deutsche Forschungsgemeinschaft (WA1477/2) (to J. W.). 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. 1–3.

¹ To whom correspondence should be addressed: Institute for Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg University, Mainz, Medical School, 55099 Mainz, Germany. Tel.: 49-6131-3925890; Fax: 49-6131-3925792; E-mail: cbehl{at}uni-mainz.de.

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