Novel cadherin-related membrane proteins, Alcadeins, enhance the X11-like protein-mediated stabilization of amyloid beta-protein precursor metabolism.
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.
Araki
Yoichi
Y
Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-ku Kita-12 Nishi-6, Sapporo 060-0812, Japan.
Tomita
Susumu
S
Yamaguchi
Haruyasu
H
Miyagi
Naomi
N
Sumioka
Akio
A
Kirino
Yutaka
Y
Suzuki
Toshiharu
T
D000544:Alzheimer Disease / Q000378:metabolism; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D002352:Carrier Proteins; D003001:Cloning, Molecular; D018076:DNA, Complementary; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins; D011233:Precipitin Tests; D017386:Sequence Homology, Amino Acid
C491636:APBA2 protein, human; D016564:Amyloid beta-Protein Precursor; C491635:Apba2 protein, mouse; D015820:Cadherins; D002352:Carrier Proteins; D018076:DNA, Complementary; D009419:Nerve Tissue Proteins