Regulation of β-Amyloid Secretion by FE65, an Amyloid Protein Precursor-binding Protein

Abstract

The principal component of Alzheimer's amyloid plaques, A␤, derives from proteolytic processing of the Alzheimer's amyloid protein precursor (APP). FE65 is a brain-enriched protein that binds to APP. Although several laboratories have characterized the APP-FE65 interaction in vitro, the possible relevance of this interaction to Alzheimer's disease has remained unclear. We demonstrate here that APP and FE65 co-localize in the endoplasmic reticulum/Golgi and possibly in endosomes. Moreover, FE65 increases translocation of APP to the cell surface, as well as both ␣APP s and A␤ secretion. The dramatic (4-fold) FE65-dependent increase in A␤ secretion suggests that agents which inhibit the interaction of FE65 with APP might reduce A␤ secretion in the brain and therefore be useful for preventing or slowing amyloid plaque formation.Amyloid plaques are one of the major hallmarks of Alzheimer's disease (AD) 1 pathology. The plaque core is largely composed of an approximately 4-kDa peptide referred to as A␤ (1, 2). Because mutations linked to AD have been shown to increase secretion of A␤ (3), secreted A␤ is believed to play a causative role in AD etiology. The precursor to A␤ is the Alzheimer's amyloid protein precursor (APP) (4,5). APP is a type I integral membrane protein, the majority of which is found in the ER/Golgi (6). A fraction of APP is transported to the plasma membrane, then routed through the endosomal/lysosomal system (6 -12).At least three unidentified proteases, known as the ␣-, ␤-, and ␥-secretases, process APP (7,(13)(14)(15)(16). The combination of ␤ and ␥ cleavages generates A␤. ␣-Secretase cleaves APP within the A␤ domain, releasing ␣APP s , the large extracellular domain. While ␣APP s is generated primarily at or en route to the plasma membrane (17), A␤ is formed in both the secretory and endocytic pathways (8). It has been suggested that the majority of secreted A␤ is made in the endocytic pathway (8).Several studies have shown that the cytoplasmic tail of APP is important for the regulation of APP metabolism and localization. The carboxyl terminus of APP contains the sequence YENPTY. NPXY is a consensus sequence for endocytosis of low density lipoprotein receptors (18). Deletion of portions of APP that contain the YENPTY sequence results in increased secretion of APP s and decreased secretion of A␤ (8, 19 -22). The effects of these deletions are thought to be the result of increased APP at the cell surface. Mutation of the second tyrosine in the YENPTY sequence to alanine also increases APP s secretion but has no effect on A␤ secretion (23). These observations suggest that secretion of A␤ and APP s may be regulated independently by signals in the cytoplasmic tail of APP.FE65 is a brain-enriched protein of unknown function (24) that binds to the cytoplasmic domain of APP. FE65 contains two types of protein-protein interaction domains: a WW domain in the amino terminus and tandem phosphotyrosine interaction domains (PIDs) in the carboxyl terminus. WW domains recognize poly-proline sequences (25), whe...

Fe65 matters: New light on an old molecule

“…Experimental evidence did not help to definitively address this point. Indeed, there are reports indicating that Ab production is increased by Fe65 overexpression (33) and reduced by Fe65 knockdown (34), whereas other studies reported that FE65 increased sAPPa and decreased Ab production (10). Apparently, the results obtained in animal models are similarly conflicting: APP knock-in mice carrying the Y682G mutation, which abolishes the binding of Fe65, showed decreased levels of Ab and a massive increase in soluble APPa (35).…”

Mint3/X11γ Is an ADP-Ribosylation Factor-dependent Adaptor that Regulates the Traffic of the Alzheimer's Precursor Protein from theTrans-Golgi Network

“…The highly conserved phosphotyrosine binding (PTB) domains in all three Mint proteins have been shown previously to bind directly to the YENPXY motif of APP (Borg et al, 1996(Borg et al, , 1998Zhang et al, 1997;Sastre et al, 1998;Tanahashi and Tabira, 1999;Tomita et al, 1999;Ho et al, 2002;Araki et al, 2003). Other PTB domain containing proteins have similarly been shown to bind APP, including the Fe65 (Sabo et al, 1999) family, Dab2 (Howell et al, 1999), JIP1b (King et al, 2004), and ARH (Noviello et al, 2003). These proteins can each impact APP traffic and processing in a variety of ways, although where they act is unknown (Selkoe, 1998;Sabo et al, 1999;Lau et al, 2000;King et al, 2003).…”

“…Other PTB domain containing proteins have similarly been shown to bind APP, including the Fe65 (Sabo et al, 1999) family, Dab2 (Howell et al, 1999), JIP1b (King et al, 2004), and ARH (Noviello et al, 2003). These proteins can each impact APP traffic and processing in a variety of ways, although where they act is unknown (Selkoe, 1998;Sabo et al, 1999;Lau et al, 2000;King et al, 2003).…”

“…Other PTB domain containing proteins have similarly been shown to bind APP, including the Fe65 (Sabo et al, 1999) family, Dab2 (Howell et al, 1999), JIP1b (King et al, 2004), and ARH (Noviello et al, 2003). These proteins can each impact APP traffic and processing in a variety of ways, although where they act is unknown (Selkoe, 1998;Sabo et al, 1999;Lau et al, 2000;King et al, 2003).Mint1/X11␣/APBA1, Mint2/X11␤/APBA2/X11-like, and Mint3/X11␥/APBA3/X11-like 2 comprise a family of proteins that share highly conserved PTB and dual PDZ domains, with divergent N termini. We have shown previously that all three Mints bind to the activated form (GTP-bound) of ADP-ribosylation factor (Arf) via both the PTB and second postsynaptic density 95/disc-large/zona occludens (PDZ) domains (Hill et al, 2003) and that Mint3 localizes to late Golgi/TGN membranes in several cell lines (Biederer and Sudhof, 2000;Hill et al, 2003).…”

Frame‐shifted amyloid precursor protein found in Alzheimer's disease and Down's syndrome increases levels of secreted amyloid β40

“…These proteins, which all bind to the intracellular C-terminal part of APP, are Fe65 (Guenette et al 1999;Sabo et al 1999), X11 Sastre et al 1998), mammalian disabled, mDab1 (Trommsdorff et al 1998;Homayouni et al 1999), JNKinteracting protein-1, JIP-1b (Matsuda et al 2001), a major brain GTP-binding protein, G o (Nishimoto et al 1993), a microtubule-interacting protein, PAT-1 (Zheng et al 1998) and APP-BP1 (Chow et al 1996). Fe65, X11, mDab1 and JIP-1b are adaptor proteins that have a phosphotyrosinebinding domain responsible for the interaction with the YENPTY motif in the cytoplasmic tail of APP.…”