N‐cadherin‐based adhesion enhances Aβ release and decreases Aβ<sub>42/40</sub> ratio

Uemura, Kazunori; Lill, Christina M.; Banks, Mary; Asada, Megumi; Aoyagi, Nobuhisa; Andō, Kōichi; Kubota, Masakazu; Kihara, Takeshi; Nishimoto, Takaaki; Sugimoto, Hachiro; Takahashi, Ryōsuke; Hyman, Bradley T.; Shimohama, Shun; Berezovska, Oksana; Kinoshita, Ayae

doi:10.1111/j.1471-4159.2008.05760.x

Cited by 22 publications

(17 citation statements)

References 30 publications

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“…CHO cells stably overexpressing Swedish mutant APP (K670M/ N770L) (APPsw/Ncad-CHO cells), in which it is possible to quantify released Aβ, were obtained [ 24 ] and maintained as described previously [ 25 , 26 ]. SH-SY5Y cells which derived from human neuroblastoma were maintained in Opti-MEM (Life technology, USA) containing 10% FBS.…”

Section: Methodsmentioning

confidence: 99%

High Fat Diet Enhances β-Site Cleavage of Amyloid Precursor Protein (APP) via Promoting β-Site APP Cleaving Enzyme 1/Adaptor Protein 2/Clathrin Complex Formation

et al. 2015

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Obesity and type 2 diabetes are risk factors of Alzheimer’s disease (AD). We reported that a high fat diet (HFD) promotes amyloid precursor protein (APP) cleavage by β-site APP cleaving enzyme 1 (BACE1) without increasing BACE1 levels in APP transgenic mice. However, the detailed mechanism had remained unclear. Here we demonstrate that HFD promotes BACE1/Adaptor protein-2 (AP-2)/clathrin complex formation by increasing AP-2 levels in APP transgenic mice. In Swedish APP overexpressing Chinese hamster ovary (CHO) cells as well as in SH-SY5Y cells, overexpression of AP-2 promoted the formation of BACE1/AP-2/clathrin complex, increasing the level of the soluble form of APP β (sAPPβ). On the other hand, mutant D495R BACE1, which inhibits formation of this trimeric complex, was shown to decrease the level of sAPPβ. Overexpression of AP-2 promoted the internalization of BACE1 from the cell surface, thus reducing the cell surface BACE1 level. As such, we concluded that HFD may induce the formation of the BACE1/AP-2/clathrin complex, which is followed by its transport of BACE1 from the cell surface to the intracellular compartments. These events might be associated with the enhancement of β-site cleavage of APP in APP transgenic mice. Here we present evidence that HFD, by regulation of subcellular trafficking of BACE1, promotes APP cleavage.

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Section: Methodsmentioning

confidence: 99%

High Fat Diet Enhances β-Site Cleavage of Amyloid Precursor Protein (APP) via Promoting β-Site APP Cleaving Enzyme 1/Adaptor Protein 2/Clathrin Complex Formation

et al. 2015

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“…N-Cadherin is another CAM that is enriched at excitatory synapses and has been implicated in AD as well as homeostatic synaptic plasticity. N-Cadherin promotes APP dimerization, modulates A β secretion, and reduces surface expression of presinilin-1 [ 131 , 132 ]. N-Cadherin also binds to the extracellular domains of GluA1 in a Ca 2+ -dependent manner and regulates GluA1 surface expression [ 251 , 252 ].…”

Section: Putative Mechanisms Underlying Defective Homeostatic Synamentioning

confidence: 99%

Emerging Link between Alzheimer’s Disease and Homeostatic Synaptic Plasticity

Jang

Chung

2016

Neural Plasticity

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Alzheimer's disease (AD) is an irreversible brain disorder characterized by progressive cognitive decline and neurodegeneration of brain regions that are crucial for learning and memory. Although intracellular neurofibrillary tangles and extracellular senile plaques, composed of insoluble amyloid-β (Aβ) peptides, have been the hallmarks of postmortem AD brains, memory impairment in early AD correlates better with pathological accumulation of soluble Aβ oligomers and persistent weakening of excitatory synaptic strength, which is demonstrated by inhibition of long-term potentiation, enhancement of long-term depression, and loss of synapses. However, current, approved interventions aiming to reduce Aβ levels have failed to retard disease progression; this has led to a pressing need to identify and target alternative pathogenic mechanisms of AD. Recently, it has been suggested that the disruption of Hebbian synaptic plasticity in AD is due to aberrant metaplasticity, which is a form of homeostatic plasticity that tunes the magnitude and direction of future synaptic plasticity based on previous neuronal or synaptic activity. This review examines emerging evidence for aberrant metaplasticity in AD. Putative mechanisms underlying aberrant metaplasticity in AD will also be discussed. We hope this review inspires future studies to test the extent to which these mechanisms contribute to the etiology of AD and offer therapeutic targets.

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“…Immunostaining-The samples for immunostaining were prepared as described elsewhere (15). After fixation, the samples were examined using a laser scanning confocal microscope, LSM 510 META (Zeiss).…”

Section: Methodsmentioning

confidence: 99%

“…MTT assay was performed using the MTT cell proliferation assay kit (Cayman) according to the manufacturer's instructions. For inhibition of N-cadherinmediated cell-cell contact, the cells were treated either with ADH-1 as indicated or with N-cadherin-neutralizing antibody (GC-4) as described elsewhere (15).…”

Section: Methodsmentioning

confidence: 99%

“…As a consequence, PS1/N-cadherin interaction at the synapse seems to be neuroprotective by facilitating the PI3K/Akt survival signaling. Recently, we demonstrated that N-cadherin promotes the cell surface expression of PS1/␥-secretase, thereby activating the PI3K/Akt/GSK3␤ signaling pathway (14) and that N-cadherin-mediated synaptic adhesion modulates A␤ secretion as well as A␤ 42/40 ratio via PS1/ N-cadherin interactions (15). Therefore, it is plausible that N-cadherin functions not only as a synaptic adhesion molecule but also as a modulator of AD pathology by affecting A␤ production and PI3K/Akt signaling.…”

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confidence: 99%

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

Andō

Uemura

Kuzuya

et al. 2011

Journal of Biological Chemistry

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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 ...

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N‐cadherin‐based adhesion enhances Aβ release and decreases Aβ_42/40 ratio

Cited by 22 publications

References 30 publications

High Fat Diet Enhances β-Site Cleavage of Amyloid Precursor Protein (APP) via Promoting β-Site APP Cleaving Enzyme 1/Adaptor Protein 2/Clathrin Complex Formation

High Fat Diet Enhances β-Site Cleavage of Amyloid Precursor Protein (APP) via Promoting β-Site APP Cleaving Enzyme 1/Adaptor Protein 2/Clathrin Complex Formation

Emerging Link between Alzheimer’s Disease and Homeostatic Synaptic Plasticity

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

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N‐cadherin‐based adhesion enhances Aβ release and decreases Aβ42/40 ratio

Cited by 22 publications

References 30 publications

High Fat Diet Enhances β-Site Cleavage of Amyloid Precursor Protein (APP) via Promoting β-Site APP Cleaving Enzyme 1/Adaptor Protein 2/Clathrin Complex Formation

High Fat Diet Enhances β-Site Cleavage of Amyloid Precursor Protein (APP) via Promoting β-Site APP Cleaving Enzyme 1/Adaptor Protein 2/Clathrin Complex Formation

Emerging Link between Alzheimer’s Disease and Homeostatic Synaptic Plasticity

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

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N‐cadherin‐based adhesion enhances Aβ release and decreases Aβ_42/40 ratio