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J. Biol. Chem., Vol. 283, Issue 37, 25492-25502, September 12, 2008

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Numb Endocytic Adapter Proteins Regulate the Transport and Processing of the Amyloid Precursor Protein in an Isoform-dependent Manner

IMPLICATIONS FOR ALZHEIMER DISEASE PATHOGENESIS^*

George A. Kyriazis, Zelan Wei, Miriam Vandermey, Dong-Gyu Jo, Ouyang Xin^¶, Mark P. Mattson^¶, and Sic L. Chan¹

From the Biomolecular Science Center, University of Central Florida, Orlando, Florida 32816, the College of Pharmacy, Sungkyunkwan University, Suwon 440-746, Korea, and the ^¶Laboratory of Neurosciences, NIA, National Institutes of Health, Intramural Research Program, Baltimore, Maryland 21224

Central to the pathogenesis of Alzheimer disease is the aberrant processing of the amyloid precursor protein (APP) to generate amyloid β-peptide (Aβ), the principle component of amyloid plaques. The cell fate determinant Numb is a phosphotyrosine binding domain (PTB)-containing endocytic adapter protein that interacts with the carboxyl-terminal domain of APP. The physiological relevance of this interaction is unknown. Mammals produce four alternatively spliced variants of Numb that differ in the length of their PTB and proline-rich region. In the current study, we determined the influence of the four human Numb isoforms on the intracellular trafficking and processing of APP. Stable expression of Numb isoforms that differ in the PTB but not in the proline-rich region results in marked differences in the sorting of APP to the recycling and degradative pathways. Neural cells expressing Numb isoforms that lack the insert in the PTB (short PTB (SPTB)) exhibited marked accumulation of APP in Rab5A-labeled early endosomal and recycling compartments, whereas those expressing isoforms with the insertion in the PTB (long PTB (LPTB)) exhibited reduced amounts of cellular APP and its proteolytic derivatives relative to parental control cells. Neither the activities of theβ- and -secretases nor the expression of APP mRNA were significantly different in the stably transfected cells, suggesting that the differential effects of the Numb proteins on APP metabolism is likely to be secondary to altered APP trafficking. In addition, the expression of SPTB-Numb increases at the expense of LPTB-Numb in neuronal cultures subjected to stress, suggesting a role for Numb in stress-induced Aβ production. Taken together, these results suggest distinct roles for the human Numb isoforms in APP metabolism and may provide a novel potential link between altered Numb isoform expression and increased Aβ generation.

Received for publication, March 14, 2008 , and in revised form, July 1, 2008.

^* This work was authored, in whole or in part, by National Institutes of Health staff. 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. 1.

¹ To whom correspondence should be addressed: Burnett School of Biomedical Sciences, University of Central Florida, 4000 Central Florida Blvd., Orlando 32816. Tel.: 407-823-1354; Fax: 407-823-0956; E-mail: schan{at}mail.ucf.edu.

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