Amyloid- (cid:1) Protein Precursor (A (cid:1) PP) Intracellular Domain-associated Protein-1 Proteins Bind to A (cid:1) PP and Modulate Its Processing in an Isoform-specific Manner*

The amyloid- (cid:1) protein precursor (A (cid:1) PP) is a type I transmembrane molecule that undergoes several finely regulated cleavage events. The physiopathological rele-vance of A (cid:1) PP 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 amy-loid- (cid:1) peptide, a 40–42 amino-acid-long protein fragment derived by A (cid:1) PP upon two sequential processing events. Mutations in the genes encoding for A (cid:1) PP 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 un-derlying A (cid:1) PP metabolism appears crucial to under-standing the basis for the onset of AD. Apart from A (cid:1) , upon processing of A (cid:1) PP other fragments are generated. The long extracellular domain is released in the extracellular space, whereas the short cytoplasmic tail, named A (cid:1) PP intracellular domain (AID) is released in-tracellularly. 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 A (cid:1) PP. Our data demonstrated that the interaction between the two molecules is regulated by alternative splicing of the AIDA-1 proteins. Furthermore, we pro-vide data supporting a possible function for AIDA-1a as a modulator of A (cid:1) PP processing. decided to eliminate the region downstream of the PTB domain by designing a specific antisense primer at the end of the PTB domain. various deletion mutants have been amplified by PCR and cloned into pcDNA3 or pEYFP-C1 primers used to amplify AIDA-1b and the various deletion mutants are 5 (AIDA-1b kid-ney modified supplemented fetal bovine stably A (cid:1) PP were in the above-described cell culture medium supplemented with 5 (cid:4) g/ml puromycin. Transient transfec- tions using FuGENE 6 Applied Science) at