The familial Alzheimer's disease gene product amyloid ␤ precursor protein (APP) is sequentially processed by ␤-and ␥-secretases to generate the A␤ peptide. The biochemical pathway leading to A␤ formation has been extensively studied since extracellular aggregates of A␤ peptides are considered the culprit of Alzheimer's disease. Aside from its pathological relevance, the biological role of APP processing is unknown. Cleavage of APP by ␥-secretase releases, together with A␤, a COOH-terminal APP intracellular domain, termed AID. This peptide has recently been identified in brain tissue of normal control and patients with sporadic Alzheimer's disease. We have previously shown that AID acts as a positive regulator of apoptosis. Nevertheless, the molecular mechanism by which AID regulates this process remains unknown. Hoping to gain clues about the function of APP, we used the yeast two-hybrid system to identify interaction between the AID region of APP and JNK-interacting protein-1 (JIP1). This molecular interaction is confirmed in vitro, in vivo by fluorescence resonance energy transfer (FRET), and in mouse brain lysates. These data provide a link between APP and its processing by ␥-secretase, and stress kinase signaling pathways. These pathways are known regulators of apoptosis and may be involved in the pathogenesis of Alzheimer's disease. The amyloid ␤ (A␤)1 peptide is the principal component of amyloid plaques in the brain of Alzheimer's disease (AD) patients (1-3). A␤ is derived from APP by two sequential proteolytic events, one in the extracellular domain (␤-secretase cleavage) (4) and one in the transmembrane domain (␥-secretase cleavage) (5). APP processing has become firmly associated with the pathogenesis of AD with the identification of missense mutations in three genes associated with familial forms of AD (FAD). The FAD mutations identified to date are found in APP itself, and in two highly homologous genes now known as presenilin 1 and presenilin 2 (PS1, PS2) (6 -9). Presenilins are a key component of a multimolecular complex with ␥-secretase activity that contains at least one other recently identified protein named nicastrin (10 -16). A common feature of all FAD mutations is that they increase the generation of A␤ peptides (especially the A␤42 form, considered to be more pathogenic than the A␤40 peptide) by accelerating the rate of APP processing by either ␤-or ␥-secretase (5, 18 -20). In addition to the A␤ peptide which is mostly released from the cell, another peptide, AID, is released into the cytoplasm as a result of the ␥-secretase cleavage. Although the role of the A␤ peptide in the pathogenesis of AD has been extensively studied, only recently have there been reports as to the role of AID. AID-like peptides have recently been identified in human brains from normal controls and cases of sporadic AD (21). AID has also been implicated in the pathology of AD by data indicating that it can independently trigger apoptosis or enhance other apoptotic stimuli (21). This may represent the mechanism by wh...

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The Amyloid-β Protein Precursor (AβPP) is a widely expressed transmembrane protein that is extensively processed in intracellular vesicular compartments and on the cell membrane. As a result of two sequential proteolytic cleavages, AβPP releases the Amyloid-β (Aβ) peptide, which accumulates in insoluble plaques in the brain of patients affected by Alzheimer's Disease (AD). Another peptide, a C-terminal fragment named AβPP Intracellular Domain (AID), is generated by AβPP processing and is released intracellularly. Several functions for AID have been proposed: pro-apoptotic peptide, regulator of calcium homeostasis, molecule involved in transcriptional regulation. Many intracellular proteins, such as Fe65, Jip-1, Shc, Numb and X11α, interact with AID and modulate its function by different mechanisms. Here we report the cloning and initial characterization of two isoforms of a novel protein that we named AID Associated protein-1a (AIDA-1a), AIDA-1b and AIDA-1b∆Ank. We show that AβPP and the AIDA-1 proteins interact in vitro, in living cells and, endogenously, in leukemia cell lines. Transfected AIDA-1a, AIDA-1b and AIDA-1b∆Ank localize in different compartments and the intracellular distribution of AIDA-1a can be modified by over-expression of AβPP. AIDA-1 proteins are expressed at high levels in the brain; thus, studying their involvement in AβPP processing and AID function might give new insights regarding a possible role for these molecules in normal brain development and in the pathogenesis of AD.