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Masato Maesako,
Kengo Uemura,
Masakazu Kubota,
Akira Kuzuya,
Kazuki Sasaki,
Naoko Hayashida, Megumi Asada-Utsugi,
Kiwamu Watanabe,
Maiko Uemura,
Takeshi Kihara,
Ryosuke Takahashi,
Shun Shimohama,
Ayae Kinoshita
[show abstract]
[hide abstract]
ABSTRACT: Accumulating evidence suggests that some dietary patterns, specifically high fat diet (HFD), increase the risk of developing sporadic Alzheimer disease (AD). Thus, interventions targeting HFD-induced metabolic dysfunctions may be effective in preventing the development of AD. We previously demonstrated that amyloid precursor protein (APP)-overexpressing transgenic mice fed HFD showed worsening of cognitive function when compared with control APP mice on normal diet. Moreover, we reported that voluntary exercise ameliorates HFD-induced memory impairment and β-amyloid (Aβ) deposition. In the present study, we conducted diet control to ameliorate the metabolic abnormality caused by HFD on APP transgenic mice and compared the effect of diet control on cognitive function with that of voluntary exercise as well as that of combined (diet control plus exercise) treatment. Surprisingly, we found that exercise was more effective than diet control, although both exercise and diet control ameliorated HFD-induced memory deficit and Aβ deposition. The production of Aβ was not different between the exercise- and the diet control-treated mice. On the other hand, exercise specifically strengthened the activity of neprilysin, the Aβ-degrading enzyme, the level of which was significantly correlated with that of deposited Aβ in our mice. Notably, the effect of the combination treatment (exercise and diet control) on memory and amyloid pathology was not significantly different from that of exercise alone. These studies provide solid evidence that exercise is a useful intervention to rescue HFD-induced aggravation of cognitive decline in transgenic model mice of AD.
Journal of Biological Chemistry 05/2012; 287(27):23024-33. · 4.77 Impact Factor
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Megumi Asada-Utsugi,
Kengo Uemura,
Yasuha Noda,
Akira Kuzuya,
Masato Maesako,
Koichi Ando,
Masakazu Kubota,
Kiwamu Watanabe,
Makio Takahashi,
Takeshi Kihara,
Shun Shimohama,
Ryosuke Takahashi,
Oksana Berezovska,
Ayae Kinoshita
[show abstract]
[hide abstract]
ABSTRACT: Sequential processing of amyloid precursor protein (APP) by β- and γ-secretase leads to the generation of amyloid-β (Aβ) peptides, which plays a central role in Alzheimer's disease pathogenesis. APP is capable of forming a homodimer through its extracellular domain as well as transmembrane GXXXG motifs. A number of reports have shown that dimerization of APP modulates Aβ production. On the other hand, we have previously reported that N-cadherin-based synaptic contact is tightly linked to Aβ production. In the present report, we investigated the effect of N-cadherin expression on APP dimerization and metabolism. Here, we demonstrate that N-cadherin expression facilitates cis-dimerization of APP. Moreover, N-cadherin expression led to increased production of Aβ as well as soluble APPβ, indicating that β-secretase-mediated cleavage of APP is enhanced. Interestingly, N-cadherin expression affected neither dimerization of C99 nor Aβ production from C99, suggesting that the effect of N-cadherin on APP metabolism is mediated through APP extracellular domain. We confirmed that N-cadherin enhances APP dimerization by a novel luciferase-complementation assay, which could be a platform for drug screening on a high-throughput basis. Taken together, our results suggest that modulation of APP dimerization state could be one of mechanisms, which links synaptic contact and Aβ production.
Journal of Neurochemistry 06/2011; 119(2):354-63. · 4.06 Impact Factor
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Koichi Ando,
Kengo Uemura,
Akira Kuzuya,
Masato Maesako, Megumi Asada-Utsugi,
Masakazu Kubota,
Nobuhisa Aoyagi,
Katsuji Yoshioka,
Katsuya Okawa,
Haruhisa Inoue,
Jun Kawamata,
Shun Shimohama,
Tetsuaki Arai,
Ryosuke Takahashi,
Ayae Kinoshita
[show abstract]
[hide abstract]
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 Aβ42 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.
Journal of Biological Chemistry 03/2011; 286(9):7619-7628. · 4.77 Impact Factor
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Koichi Ando,
Kengo Uemura,
Akira Kuzuya,
Masato Maesako, Megumi Asada-Utsugi,
Masakazu Kubota,
Nobuhisa Aoyagi,
Katsuji Yoshioka,
Katsuya Okawa,
Haruhisa Inoue,
Jun Kawamata,
Shun Shimohama,
Tetsuaki Arai,
Ryosuke Takahashi,
Ayae Kinoshita
[show abstract]
[hide abstract]
ABSTRACT: Synaptic loss, which strongly correlates with the decline of cognitive function, is one of the pathological hallmarks of Alzheimer's
disease (AD). N-cadherin is a cell-adhesion molecule essential for synaptic contact and is involved in intracellular signaling
pathway at the synapse. Here we report that the functional disruption of N-cadherin-mediated cell contact activated p38 mitogen
activated protein kinase (MAPK) in murine primary neurons, followed by neuronal death. We further observed that treatment
with Aβ42 decreased cellular N-cadherin expression through N-methyl-D-aspartate (NMDA) receptors accompanied by increased
phosphorylation of both p38MAPK and tau in murine primary neurons. Moreover, expression levels of phosphorylated p38MAPK were
negatively correlated with that of N-cadherin in human brains. Proteomic analysis of human brains identified a novel interaction
between N-cadherin and c-Jun NH2-terminal kinase (JNK)-associated leucine zipper protein (JLP), a scaffolding protein involved
in p38MAPK signaling pathway. We demonstrated that N-cadherin expression had an inhibitory effect on JLP-mediated p38MAPK
signal activation by decreasing the interaction between JLP and p38MAPK in COS7 cells. Also, this study demonstrated a novel
physical and functional association between N-cadherin and p38MAPK 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 AD brain.
Journal of Biological Chemistry 12/2010; · 4.77 Impact Factor
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Koichi Ando,
Kengo Uemura,
Akira Kuzuya,
Masato Maesako, Megumi Asada-Utsugi,
Masakazu Kubota,
Nobuhisa Aoyagi,
Katsuji Yoshioka,
Katsuya Okawa,
Haruhisa Inoue,
Jun Kawamata,
Shun Shimohama,
Tetsuaki Arai,
Ryosuke Takahashi,
Ayae Kinoshita
[show abstract]
[hide abstract]
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.
Journal of Biological Chemistry 12/2010; 286(9):7619-28. · 4.77 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Chronic cerebral ischemia may accelerate clinicopathological changes in Alzheimer's disease. We have examined whether chronic cerebral hypoperfusion accelerates amyloid beta deposition in amyloid protein precursor transgenic (APP-Tg) mouse. At 5, 8, and 11 months of age, C57Bl/6J male mice overexpressing a mutant form of the human APP bearing the both Swedish (K670N/M671L) and the Indiana (V717F) mutations (APPSwInd) and their litterrmates were subjected to either sham operation or bilateral carotid artery stenosis (BCAS) using microcoils with an internal diameter of 0.18 mm (short-period group). One month after the sham operation or BCAS, these animals were examined by immunohistochemistry for glial fibrillary acidic protein, amyloid beta(1-40) (Abeta(1-40)), amyloid beta(1-42) (Abeta(1-42)), as well as Western blotting and filter assay for Abeta. Another batch of the littermates of APPSwInd mice were subjected to either sham operation or BCAS at 3 months and were examined in the same manner after survival for 9 months (long-period group). In the BCAS-treated group, the white matter was rarefied and astroglia was proliferated. Amyloid beta(1-40) immunoreactivity was found in a few axons in the white matter after BCAS, whereas Abeta(1-42) was accumulated in the scattered cortical neurons and the axons at ages of 6 months and thereafter in the short- and long-period groups. In the neuropil, both Abeta(1-40) and Abeta(1-42) were deposited in the sham-operated and BCAS-treated mice at ages of 9 and 12 months. There were no differences between the short-period group at ages of 12 months and the long-period group. Filter assay showed an increase of Abeta fibrils in the extracellular enriched fraction. Taken together, chronic cerebral hypoperfusion increased Abeta fibrils and induced Abeta deposition in the intracellular compartment and, therefore, may accelerate the pathological changes of Alzheimer's disease.
Brain research 08/2009; 1294:202-10. · 2.46 Impact Factor
