Journal of Biological Chemistry
Volume 276, Issue 46, 16 November 2001, Pages 43343-43350
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PROTEIN STRUCTURE AND FOLDING
Multiple Effects of Aspartate Mutant Presenilin 1 on the Processing and Trafficking of Amyloid Precursor Protein*

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PS1 deficiency and expression of PS1 with substitutions of two conserved transmembrane aspartate residues (“PS1 aspartate variants”) leads to the reduction of Aβ peptide secretion and the accumulation of amyloid precursor protein (APP) C-terminal fragments. To define the nature of the “dominant negative” effect of the PS1 aspartate variants, we stably expressed PS1 harboring aspartate to alanine substitutions at codons 257 (D257A) or 385 (D385A), singly or in combination (D257A/D385A), in mouse neuroblastoma, N2a cells. Expression of the PS1 aspartate variants resulted in marked accumulation of intracellular and cell surface APP C-terminal fragments. While expression of the D385A PS1 variant reduced the levels of secreted Aβ peptides, we now show that neither the PS1 D257A nor D257A/D385A variants impair Aβ production. Surprisingly, the stability of both immature and mature forms of APP is dramatically elevated in cells expressing PS1 aspartate variants, commensurate with an increase in the cell surface levels of APP. These findings lead us to conclude that the stability and trafficking of APP can be profoundly modulated by coexpression of PS1 with mutations at aspartate 257 and aspartate 385.

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Published, JBC Papers in Press, September 19, 2001, DOI 10.1074/jbc.M108245200

*

This study was supported by National Institutes of Health Grant AG14248.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence and reprint requests should be addressed: Dept. of Neurobiology, Pharmacology, and Physiology University of Chicago, Abbott 510, 947 E. 58th St., Chicago, IL 60637. Tel.: 773-834-9186; Fax: 773-702-3774; E-mail: [email protected].