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J. Biol. Chem., Vol. 279, Issue 47, 49105-49112, November 19, 2004

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Amyloid- Protein Precursor (APP) Intracellular Domain-associated Protein-1 Proteins Bind to APP and Modulate Its Processing in an Isoform-specific Manner^*

Enrico Ghersi, Cristiana Noviello, and Luciano D'Adamio¶

From the Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461

The amyloid- protein precursor (APP) is a type I transmembrane molecule that undergoes several finely regulated cleavage events. The physiopathological relevance of APP derives from the fact that its aberrant processing strongly correlates with the onset of Alzheimer's disease (AD). AD is a neurodegenerative disorder characterized by neuronal cell death, loss of synapses, and deposition of misfolded protein plaques in the brain; the main constituent of these plaques is the amyloid- peptide, a 40–42 amino-acid-long protein fragment derived by APP upon two sequential processing events. Mutations in the genes encoding for APP and some of the enzymes responsible for its processing are strongly associated with familial forms of early onset AD. Therefore, the elucidation of the mechanisms underlying APP metabolism appears crucial to understanding the basis for the onset of AD. Apart from A, upon processing of APP other fragments are generated. The long extracellular domain is released in the extracellular space, whereas the short cytoplasmic tail, named APP intracellular domain (AID) is released intracellularly. AID appears be involved in several cellular processes, apoptosis, calcium homeostasis, and transcriptional regulation. We have recently reported the cloning and characterization of different isoforms of AID associated protein-1 (AIDA-1), a novel AID-binding protein. Here we further analyzed the interaction between several AIDA-1 isoforms and the cytoplasmic tail of APP. Our data demonstrated that the interaction between the two molecules is regulated by alternative splicing of the AIDA-1 proteins. Furthermore, we provide data supporting a possible function for AIDA-1a as a modulator of APP processing.

Received for publication, May 12, 2004 , and in revised form, August 23, 2004.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY620824.

^* This work was supported by an Alzheimer's Disease Research Grant A2003-076, National Institutes of Health Grants NIH RO1 AG 22024 and NIH RO1 AG21588 (to L. D.), and by a Telethon Italia grant (to C. N.). 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.

Present address: Dipartimento di Biochimica e Biotecnologie Mediche, Universita' Degli Studi di Napoli Federico II, CEINGE Biotecnologie Avanzate, Via Comunale Margherita 482, 80145 Naples, Italy.

^¶ To whom correspondence should be addressed: Albert Einstein College of Medicine, Dept. of Microbiology and Immunology, 1300 Morris Park Ave., Bronx, NY 10461. E-mail: ldadamio{at}aecom.yu.edu.

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