Intracellular Trafficking of the Amyloid β-Protein Precursor (APP) Regulated by Novel Function of X11-Like

Abstract

BackgroundAmyloid β (Aβ), a causative peptide of Alzheimer's disease, is generated by intracellular metabolism of amyloid β-protein precursor (APP). In general, mature APP (mAPP, N- and O-glycosylated form) is subject to successive cleavages by α- or β-, and γ-secretases in the late protein secretory pathway and/or at plasma membrane, while immature APP (imAPP, N-glycosylated form) locates in the early secretory pathway such as endoplasmic reticulum or cis-Golgi, in which imAPP is not subject to metabolic cleavages. X11-like (X11L) is a neural adaptor protein composed of a phosphotyrosine-binding (PTB) and two C-terminal PDZ domains. X11L suppresses amyloidogenic cleavage of mAPP by direct binding of X11L through its PTB domain, thereby generation of Aβ lowers. X11L expresses another function in the regulation of intracellular APP trafficking.MethodologyIn order to analyze novel function of X11L in intracellular trafficking of APP, we performed a functional dissection of X11L. Using cells expressing various domain-deleted X11L mutants, intracellular APP trafficking was examined along with analysis of APP metabolism including maturation (O-glycosylation), processing and localization of APP.ConclusionsX11L accumulates imAPP into the early secretory pathway by mediation of its C-terminal PDZ domains, without being bound to imAPP directly. With this novel function, X11L suppresses overall APP metabolism and results in further suppression of Aβ generation. Interestingly some of the accumulated imAPP in the early secretory pathway are likely to appear on plasma membrane by unidentified mechanism. Trafficking of imAPP to plasma membrane is observed in other X11 family proteins, X11 and X11L2, but not in other APP-binding partners such as FE65 and JIP1. It is herein clear that respective functional domains of X11L regulate APP metabolism at multiple steps in intracellular protein secretory pathways.

Insulin Reverses the High-Fat Diet–Induced Increase in Brain Aβ and Improves Memory in an Animal Model of Alzheimer Disease

“…This observation is supported by previous in vitro studies showing a decrease BACE concentration following addition of insulin to cell culture (52). Second, insulin administration increased X11a (14% CD and 37% HFD), an adaptator protein that binds to APP and reduces its amyloidogenic cleavage (53,54), which was inversely correlated with insoluble Ab42 (r 2 = 0.13) (Fig. 4E and F).…”

Retention in Endoplasmic Reticulum 1 (RER1) Modulates Amyloid-β (Aβ) Production by Altering Trafficking of γ-Secretase and Amyloid Precursor Protein (APP)

“…Because A␤ is predominantly generated in the late secretory and endosomal pathways (31,59,60), positive and negative control of the transport of APP and ␥-secretase in the ER and Golgi impacts the efficiency of A␤ production. Studies using brefeldin A, which causes a rapid redistribution of the Golgi apparatus into the ER (61), have shown that immature APP accumulates, cell surface APP decreases, and A␤ secretion decreases as a result of collapse of the Golgi network (62)(63)(64). BACE1 overexpression studies also suggested that A␤ production is highly dependent on the specific subcellular localization of APP and BACE1 (65).…”

Recruitment of the Mint3 Adaptor Is Necessary for Export of the Amyloid Precursor Protein (APP) from the Golgi Complex

“…We have previously shown that the monomeric adaptor Mint3 is important for export from the Golgi, as depletion of Mint3 or truncation of the tail of APP to remove the YENPTY motif alter APP traffic (25). The shorter NPXY motif is found within the YENPTY motif and binds to Fe65 and Dab2 (19), although reports vary as to the effect of Fe65 on the processing of APP (26,27). Snx17 also binds to APP through the YENPTY motif at early endosomes to affect A␤ production (28).…”