Previously we found that X11-like protein (X11L) associates with amyloid ␤-protein precursor (APP). X11L stabilizes APP metabolism and suppresses the secretion of the amyloid ␤-protein (A␤) that are the pathogenic agents of Alzheimer's disease (AD). Here we found that Alcadein (Alc), a novel membrane protein family that contains cadherin motifs and originally reported as calsyntenins, also interacted with X11L. Alc was abundant in the brain and occurred in the same areas of the brain as X11L. X11L could simultaneously associate with APP and Alc, resulting in the formation of a tripartite complex in brain. The tripartite complex stabilized intracellular APP metabolism and enhanced the X11L-mediated suppression of A␤ secretion that is due to the retardation of intracellular APP maturation. X11L and Alc also formed another complex with C99, a carboxyl-terminal fragment of APP cleaved at the ␤-site (CTF␤). The formation of the Alc⅐X11L⅐C99 complex inhibited the interaction of C99 with presenilin, which strongly suppressed the ␥-cleavage of C99. In AD patient brains, Alc and APP were particularly colocalized in dystrophic neurites in senile plaques. Deficiencies in the X11L-mediated interaction between Alc and APP and/or CTF␤ enhanced the production of A␤, which may be related to the development or progression of AD.The production, aggregation, and accumulation of amyloid ␤-protein (A␤) 1 in the brain are initial steps in the pathogenesis of Alzheimer's disease (AD). A␤ is generated by the intracellular processing of amyloid ␤-protein precursor (APP). Major proteolytic processing of APP generates a large extracellular amino-terminal domain (sAPP␣) and a truncated carboxyl-terminal fragment (CTF␣) by the digestion of ␣-secretase, which cleaves APP at the ␣-site within the A␤ domain. Another form of proteolytic processing occurring at the ␤-site, by ␤-secretase (or BACE), gives rise to low levels of sAPP␤ and a carboxylterminal fragment (CTF␤) including the entire A␤ domain. Both CTF␣ and CTF␤ are further cleaved by ␥-secretase (presenilin (PS) complex) and generate the p3 peptide and A␤, respectively (1, 2). A minority of AD cases fall into the familial category in which the overproduction of A␤ appears to be due to mutations in genes encoding APP or PS (3). However, most AD cases are of the sporadic type (SAD) in which mutations in APP-or PS-encoding genes do not occur. The mechanisms that lead to the overproduction of A␤ in SAD cases must therefore involve alternative mechanisms that cause the production, accumulation, and degradation of A␤ (4 -6). These mechanisms are currently being investigated intensively.APP is a type I membrane protein (7). Immature APP (Nglycosylated form) is localized in the endoplasmic reticulum and cis-Golgi, whereas mature APP (N-and O-glycosylated form) is localized to compartments following trans-Golgi and on the plasma membrane. The cytoplasmic domain of APP (APPcyt), through its interactions with cytoplasmic proteins and/or its conformational changes due to phosphorylation (8 -13), pl...

The Alcadeins (Alcs)/calsyntenins and the amyloid ␤-protein precursor (APP) associate with each other in the brain by binding via their cytoplasmic domains to X11L (the X11-like protein). We previously reported that the formation of this APP-X11L-Alc tripartite complex suppresses the metabolic cleavages of APP. We show here that the metabolism of the Alcs markedly resembles that of APP. The Alcs are subjected to a primary cleavage event that releases their extracellular domain. Alcs then undergo a secondary presenilin-dependent ␥-cleavage that leads to the secretion of the amyloid ␤-protein-like peptide and the liberation of an intracellular domain fragment (AlcICD). However, when Alc is in the tripartite complex, it escapes from these cleavages, as does APP. We also found that AlcICD suppressed the FE65-dependent gene transactivation activity of the APP intracellular domain fragment, probably because AlcICD competes with the APP intracellular domain fragment for binding to FE65. We propose that the Alcs and APP are coordinately metabolized in neurons and that their cleaved cytoplasmic fragments are reciprocally involved in the regulation of FE65-dependent gene transactivation. Any imbalance in the metabolism of Alcs and APP may influence the FE65-dependent gene transactivation, which together with increased secretion of amyloid ␤-protein may contribute to neural disorders.The deposition and accumulation of amyloid ␤-protein (A␤) 1 in the human brain are hallmarks of Alzheimer's disease (AD)(1). Amyloid ␤-protein precursor (APP) is the precursor of A␤. It has a receptor-like transmembrane protein structure that consists of an extracellular domain, a transmembrane domain, and a short carboxyl-terminal cytoplasmic domain (2). The cytoplasmic domain of APP controls its metabolism and various physiological functions by interacting with cytoplasmic adaptor proteins (3-8). One of these adaptor proteins is X11L (the X11-like protein), which associates with the cytoplasmic domain of APP and stabilizes APP metabolism (5, 9). During our previous research that aimed to reveal the molecular mechanism by which X11L regulates APP metabolism, we found that the Alcadeins, which form cadherin-related membrane protein family, are X11-and X11L-binding proteins (9). These proteins are also known as calsyntenins, which were originally isolated as postsynaptic Ca 2ϩ -binding membrane proteins, but whose functions were not identified (10, 11). The Alcadeins (Alcs) consist of two Alc␣ isoforms (Alc␣1 and Alc␣2) and Alc␤ and Alc␥, all of which are type I transmembrane proteins and contain a conserved X11L-binding motif in their single cytoplasmic domains, similar to APP (9).Alc does not directly interact with the cytoplasmic domain of APP. Rather, the association between the two molecules is bridged by the phosphotyrosine interaction domain of X11L. This results in the formation of a tripartite complex in the brain (9). The formation of this complex enhances the X11L-mediated stabilization of APP metabolism and suppresses the generation...

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