title: N-cadherin regulates p38 MAPK signaling via association with JNK-associated leucine zipper protein: implications for neurodegeneration in Alzheimer disease.
abstract: Synaptic loss, which strongly correlates with the decline of cognitive function, is one of the pathological hallmarks of Alzheimer disease. N-cadherin is a cell adhesion molecule essential for synaptic contact and is involved in the intracellular signaling pathway at the synapse. Here we report that the functional disruption of N-cadherin-mediated cell contact activated p38 MAPK in murine primary neurons, followed by neuronal death. We further observed that treatment with Aβ(42) decreased cellular N-cadherin expression through NMDA receptors accompanied by increased phosphorylation of both p38 MAPK and Tau in murine primary neurons. Moreover, expression levels of phosphorylated p38 MAPK were negatively correlated with that of N-cadherin in human brains. Proteomic analysis of human brains identified a novel interaction between N-cadherin and JNK-associated leucine zipper protein (JLP), a scaffolding protein involved in the p38 MAPK signaling pathway. We demonstrated that N-cadherin expression had an inhibitory effect on JLP-mediated p38 MAPK signal activation by decreasing the interaction between JLP and p38 MAPK in COS7 cells. Also, this study demonstrated a novel physical and functional association between N-cadherin and p38 MAPK and suggested neuroprotective roles of cadherin-based synaptic contact. The dissociation of N-cadherin-mediated synaptic contact by Aβ may underlie the pathological basis of neurodegeneration such as neuronal death, synaptic loss, and Tau phosphorylation in Alzheimer disease brain.
authors.affiliation: School of Human Health Sciences, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Ando
authors.forename: Kengo
authors.initials: K
authors.lastname: Uemura
authors.forename: Akira
authors.initials: A
authors.lastname: Kuzuya
authors.forename: Masato
authors.initials: M
authors.lastname: Maesako
authors.forename: Megumi
authors.initials: M
authors.lastname: Asada-Utsugi
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kubota
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Aoyagi
authors.forename: Katsuji
authors.initials: K
authors.lastname: Yoshioka
authors.forename: Katsuya
authors.initials: K
authors.lastname: Okawa
authors.forename: Haruhisa
authors.initials: H
authors.lastname: Inoue
authors.forename: Jun
authors.initials: J
authors.lastname: Kawamata
authors.forename: Shun
authors.initials: S
authors.lastname: Shimohama
authors.forename: Tetsuaki
authors.initials: T
authors.lastname: Arai
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.forename: Ayae
authors.initials: A
authors.lastname: Kinoshita
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D019556:COS Cells; D015820:Cadherins / Q000378:metabolism*; D002522:Chlorocebus aethiops; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D016350:Leucine Zippers / Q000502:physiology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009842:Oligopeptides / Q000378:metabolism; D010456:Peptides, Cyclic / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D040901:Proteomics; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C518575:ADH-1 pepide; D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; C050361:CDH2 protein, human; D015820:Cadherins; C489083:Cdh2 protein, mouse; D009842:Oligopeptides; D010456:Peptides, Cyclic; D016194:Receptors, N-Methyl-D-Aspartate; C111047:SPAG9 protein, human; C468928:Spag9 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases