N-cadherin Regulates p38 MAPK Signaling via Association with JNK-associated Leucine Zipper Protein

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 A␤ 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 cadherinbased synaptic contact. The dissociation of N-cadherin-mediated synaptic contact by A␤ may underlie the pathological basis of neurodegeneration such as neuronal death, synaptic loss, and Tau phosphorylation in Alzheimer disease brain.Alzheimer disease (AD) 2 is pathologically characterized by the presence of amyloid ␤-peptide (A␤) and neurofibrillary tangles in the neocortex and hippocampus. Insoluble A␤ fibrillar aggregates found in senile plaques have long been considered to cause the neurodegeneration of AD. On the other hand, synaptic loss is another pathological hallmark of AD, which strongly correlates with the severity of cognitive impairment better than senile plaques or neurofibrillary tangles (1). Interestingly, recent studies from AD mouse models have shown that learning impairment and synaptic dysfunction become apparent before the formation of plaques, suggesting the hypothesis that soluble A␤ causes "synaptic failure" before plaques develop and neuron death occurs (2). Converging lines of evidence suggest that natural soluble A␤ oligomers trigger synaptic loss (3). Thus, in addition to the investigation of molecular mechanisms, which develop senile plaques and neurofibrillary tangles, research focusing on synaptic dysfunction is important to clarify the earliest pathology in AD.Presenilin (PS) 1/2 is the essential catalytic component of ␥-secretase proteolytic complex (4, 5), which is responsible for the final cleavage of amyloid precursor protein to generate A␤ peptides. Mutations in PS1 have been known as the most common cause of autosomal dominant familial Alzheimer disease (6 -8). Interestingly, PS1 binds to N-cadherin, which is an essential molecule for synaptic contact and is abundantly localized in hippocampal synapses ...

Rare autosomal copy number variations in early-onset familial Alzheimer’s disease

“…60 Moreover, dissociation of N-cadherin-mediated synaptic contact by Ab has been proposed to cause neuronal cell death, synaptic loss and tau phosphorylation in AD brain. 61 Two affected siblings in family ND6 show the presence of FAD-CNV6, a 0.73-Mb intergenic gain in CN. EPHA6 is located 0.33-Mb telomeric and the only described gene in close proximity.…”

D-Serine in Neuropsychiatric Disorders: New Advances

“…A increases NMDAR activity [143,144] and induces inwards Ca 2+ current and neurotoxicity [145]. Reciprocally, NMDAR activation stimulates A production [146][147][148] and A associated synaptic loss may be NMDAR-dependent [149].…”

SPAG9 is overexpressed in osteosarcoma, and regulates cell proliferation and invasion through regulation of JunD

“…Sperm-associated antigen 9 (SPAG9) was originally identified as a novel member of the CT antigen family, and functions as a scaffolding protein involved in the activation of the c-Jun NH2-terminal kinase (JNK) signaling pathway (8)(9)(10)(11)(12). Previous studies have reported that SPAG9 is overexpressed in various types of human cancer, including breast, thyroid and cervical cancer, and colorectal carcinoma (13)(14)(15)(16)(17).…”