Novel Cadherin-related Membrane Proteins, Alcadeins, Enhance the X11-like Protein-mediated Stabilization of Amyloid β-Protein Precursor Metabolism

Yoichi Araki,Susumu Tomita,Haruyasu Yamaguchi,Naomi Miyagi,Akio Sumioka,Yutaka Kirino,Toshiharu Suzuki

doi:10.1074/jbc.m306024200

Abstract

Previously we found that X11-like protein (X11L) associates with amyloid beta-protein precursor (APP). X11L stabilizes APP metabolism and suppresses the secretion of the amyloid beta-protein (Abeta) 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 Abeta 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 beta-site (CTFbeta). The formation of the Alc.X11L.C99 complex inhibited the interaction of C99 with presenilin, which strongly suppressed the gamma-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 CTFbeta enhanced the production of Abeta, which may be related to the development or progression of AD.

Highlights

We found that X11-like protein (X11L) associates with amyloid ␤-protein precursor (APP)
X11 and X11L are thought to be fragment of APP cleaved at ␤-site; C99, CTF␤ fragment expressed as CTF␤ construct; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1propanesulfonic acid; GM-130, 130-kDa Golgi matrix protein; GST, glutathione S-transferase; HA, hemagglutinin; KHC, kinesin heavy chain; PDZ, repeated sequences in the brain-specific protein PSD-95, the Drosophila septate junction protein disks-large, and the epithelial tight junction protein ZO-1; PS, presenilin; sAPP, large extracellular amino-terminal domain truncated at the ␣- and/or the ␤-site; SYT, synaptotagmin; X11L, X11-like protein; h, human; XB31, X11L-binding protein clone number 31; sporadic type (SAD), sporadic Alzheimer’s disease (AD); APPcyt, cytoplasmic domain of APP; PI, phosphotyrosine interaction; HEK, human kidney embryonic; phosphatebuffered saline (PBS), phosphate-buffered saline; ELISA, enzyme-linked immunosorbent assay
The mechanisms involved in the development of familial AD involve mutations in APP and PS that appear to increase A␤ production and cause the early onset of dementia [1,2,3]

Summary

Introduction

We found that X11-like protein (X11L) associates with amyloid ␤-protein precursor (APP). 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. X11 and X11L are thought to be fragment of APP cleaved at ␤-site; C99, CTF␤ fragment expressed as CTF␤ construct; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1propanesulfonic acid; GM-130, 130-kDa Golgi matrix protein; GST, glutathione S-transferase; HA, hemagglutinin; KHC, kinesin heavy chain; PDZ, repeated sequences in the brain-specific protein PSD-95, the Drosophila septate junction protein disks-large, and the epithelial tight junction protein ZO-1; PS, presenilin; sAPP, large extracellular amino-terminal domain truncated at the ␣- and/or the ␤-site; SYT, synaptotagmin; X11L, X11-like protein; h, human; XB31, X11L-binding protein clone number 31; SAD, sporadic AD; APPcyt, cytoplasmic domain of APP; PI, phosphotyrosine interaction; HEK, human kidney embryonic; PBS, phosphate-buffered saline; ELISA, enzyme-linked immunosorbent assay

Methods

Results

Conclusion