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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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Masato Maesako,
Kengo Uemura, Akira Kuzuya,
Kazuki Sasaki,
Megumi Asada,
Kiwamu Watanabe,
Koichi Ando,
Masakazu Kubota,
Haruhiko Akiyama,
Ryosuke Takahashi,
Takeshi Kihara,
Shun Shimohama,
Ayae Kinoshita
[show abstract]
[hide abstract]
ABSTRACT: We have recently reported that Presenilin 1 (PS1), a causative gene of familial Alzheimer disease (AD), down-regulates the expression level of insulin receptor (IR) as well as its signaling through a γ-secretase-independent pathway. PS1 is phosphorylated by glycogen synthase kinase 3 β at the serine 353 and 357 residues. The main purpose of the present study was to clarify the effect of PS1 phosphorylation on IR/insulin signaling. Here, we demonstrate that the pseudo-phosphorylation mutant of PS1 inhibited IR transcription and reduced IR expression compared with wild-type PS1. Importantly, there was a decrease in expression of IR in AD brains, and the phosphorylation ratio of PS1 was negatively correlated with IR level in human brain samples. In the data from mouse models of AD, IR reduction was not observed at the pre-Aβ deposition stage but became apparent in that of post-Aβ deposition. Together with our previous reports, these results suggest that phosphorylated PS1 can promote the down-regulation of insulin signaling, which may be a positive feed-forward mechanism inhibiting insulin signaling. As insulin resistance is reported to be a risk factor for sporadic AD, this PS1-mediated regulatory mechanism of brain insulin signaling may be causally associated with AD pathology.
Journal of Neurochemistry 03/2012; 121(6):964-73. · 4.06 Impact Factor
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Masato Maesako,
Kengo Uemura,
Masakazu Kubota, Akira Kuzuya,
Kazuki Sasaki,
Megumi Asada,
Kiwamu Watanabe,
Naoko Hayashida,
Masafumi Ihara,
Hidefumi Ito,
Shun Shimohama,
Takeshi Kihara,
Ayae Kinoshita
[show abstract]
[hide abstract]
ABSTRACT: The pathogenesis of Alzheimer's disease (AD) is tightly associated with metabolic dysfunctions. In particular, a potential link between type 2 diabetes (T2DM) and AD has been suggested epidemiologically, clinically, and experimentally, and some studies have suggested that exercise or dietary intervention reduces risk of cognitive decline. However, there is little solid molecular evidence for the effective intervention of metabolic dysfunctions for prevention of AD. In the present study, we established the AD model mice with diabetic conditions through high-fat diet (HFD) to examine the effect of environmental enrichment (EE) on HFD-induced AD pathophysiology. Here, we demonstrated that HFD markedly deteriorated memory impairment and increased β-amyloid (Aβ) oligomers as well as Aβ deposition in amyloid precursor protein (APP) transgenic mice, which was reversed by exposure to an enriched environment for 10 weeks, despite the continuation of HFD. These studies provide solid evidence that EE is a useful intervention to ameliorate behavioral changes and AD pathology in HFD-induced aggravation of AD symptoms in APP transgenic mice.
Neurobiology of aging 12/2011; 33(5):1011.e11-23. · 5.94 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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[show abstract]
[hide abstract]
ABSTRACT: Presenilin (PS), a causative molecule of familial Alzheimer disease, acts as a crucial component of the γ-secretase complex, which is required to cleave type I transmembrane proteins such as amyloid precursor protein and Notch. However, it also functions through γ-secretase-independent pathways. Recent reports suggested that PS could regulate the expression level of cell surface receptors, including the PDGF and EGF receptors, followed by modulating their downstream pathways via γ-secretase-independent mechanisms. The main purpose of this study was to clarify the effect of PS on expression of the insulin receptor (IR) as well as on insulin signaling. Here, we demonstrate that PS inhibited IR transcription and reduced IR expression, and this was followed by down-regulation of insulin signaling. Moreover, we suggest that neither γ-secretase activity nor Wnt/β-catenin signaling can reduce the expression of IR, but a PS-mediated increase in the intracellular Ca(2+) level can be associated with it. These results clearly indicate that PS can functionally regulate insulin signaling by controlling IR expression.
Journal of Biological Chemistry 05/2011; 286(28):25309-16. · 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 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: Recently, insulin signaling has been highlighted in the pathology of Alzheimer's disease (AD). Although the association between insulin signaling and Tau pathology has been investigated in several studies, the interaction between insulin signaling and Presenilin 1 (PS1), a key molecule of amyloid beta (Abeta) pathology, has not been elucidated so far. In this study, we demonstrated that insulin inhibited PS1 phosphorylation at serine residues (serine 353, 357) via phosphatidylinositol 3-kinase (PI3K)/Akt signal pathway and strengthened the trimeric complex of PS1/N-cadherin/beta-catenin, consequently relocalizing PS1 to the cell surface. Since our recent report suggests that PS1/N-cadherin/beta-catenin complex regulates Abeta production, it is likely that insulin signaling affects Abeta pathology by regulating PS1 localization.
Neuroscience Letters 10/2010; 483(3):157-61. · 2.11 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: gamma-Secretase is an enzymatic complex, composed of presenilin 1 (PS1), nicastrin, pen-2, and aph-1, and is responsible for the intramembranous cleavage of various type-I membrane proteins. The level of each component is tightly regulated in a cell via proteasomal degradation. On the other hand, it has previously been reported that PS1/gamma-secretase is involved in the activation of phosphatidylinositol-3 kinase/Akt (PI3K/Akt) pathway. PI3K is inhibited in Alzheimer's disease (AD) brain, whereas the effects of PI3K inhibition on the metabolism of PS1/gamma-secretase have not been elucidated. Here, we demonstrate that the treatment of neurons with PI3K inhibitors leads to increased levels of PS1/gamma-secretase components through an inhibitory effect on their degradation. Moreover, PI3K inhibition accelerated ubiquitination of PS1. We further show the evidence that the PS1 ubiquitination after PI3K inhibition is represented by the multiple mono-ubiquitination, instead of poly-ubiquitination. Accordingly, treatment of cells with PI3K inhibitor led to a differential intracellular redistribution of PS1 from the one observed after the proteasomal inhibition. These results suggest that PI3K inhibition may trigger the multiple mono-ubiquitination of PS1, which precludes the degradation of PS1/gamma-secretase through the proteasomal pathway. Since PS1/gamma-secretase is deeply involved in the production of Abeta protein, a deeper knowledge into its metabolism could contribute to a better elucidation of AD pathogenesis.
Biochemical and Biophysical Research Communications 12/2009; 391(2):1240-5. · 2.48 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Presenilin 1, a causative gene product of familial Alzheimer disease, has been reported to be localized mainly in the endoplasmic reticulum and Golgi membranes. However, endogenous Presenilin 1 also localizes at the plasma membrane as a biologically active molecule. Presenilin 1 interacts with N-cadherin/beta-catenin to form a trimeric complex at the synaptic site through its loop domain, whose serine residues (serine 353 and 357) can be phosphorylated by glycogen synthase kinase 3beta. Here, we demonstrate that cell-surface expression of Presenilin 1/gamma-secretase is enhanced by N-cadherin-based cell-cell contact. Physical interaction between Presenilin 1 and N-cadherin/beta-catenin plays an important role in this process. Glycogen synthase kinase 3beta-mediated phosphorylation of Presenilin 1 reduces its binding to N-cadherin, thereby down-regulating its cell-surface expression. Moreover, reduction of the Presenilin 1.N-cadherin.beta-catenin complex formation leads to an impaired activation of contact-mediated phosphatidylinositol 3-kinase/Akt cell survival signaling. Furthermore, phosphorylation of Presenilin 1 hinders epsilon-cleavage of N-cadherin, whereas epsilon-cleavage of APP remained unchanged. This is the first report that clarifies the regulatory mechanism of Presenilin 1/gamma-secretase with respect to its subcellular distribution and its differential substrate cleavage. Because the cleavage of various membrane proteins by Presenilin 1/gamma-cleavage is involved in cellular signaling, glycogen synthase kinase 3beta-mediated phosphorylation of Presenilin 1 should be deeply associated with signaling functions. Our findings indicate that the abnormal activation of glycogen synthase kinase 3beta can reduce neuronal viability and synaptic plasticity via modulating Presenilin 1/N-cadherin/beta-catenin interaction and thus have important implications in the pathophysiology of Alzheimer disease.
Journal of Biological Chemistry 05/2007; 282(21):15823-32. · 4.77 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Presenilin 1, a causative gene product of familial Alzheimer disease, has been reported to be localized mainly in the endoplasmic
reticulum and Golgi membranes. However, endogenous Presenilin 1 also localizes at the plasma membrane as a biologically active
molecule. Presenilin 1 interacts with N-cadherin/β-catenin to form a trimeric complex at the synaptic site through its loop
domain, whose serine residues (serine 353 and 357) can be phosphorylated by glycogen synthase kinase 3β. Here, we demonstrate
that cell-surface expression of Presenilin 1/γ-secretase is enhanced by N-cadherin-based cell-cell contact. Physical interaction
between Presenilin 1 and N-cadherin/β-catenin plays an important role in this process. Glycogen synthase kinase 3β-mediated
phosphorylation of Presenilin 1 reduces its binding to N-cadherin, thereby down-regulating its cell-surface expression. Moreover,
reduction of the Presenilin 1·N-cadherin·β-catenin complex formation leads to an impaired activation of contact-mediated phosphatidylinositol
3-kinase/Akt cell survival signaling. Furthermore, phosphorylation of Presenilin 1 hinders ϵ-cleavage of N-cadherin, whereas
ϵ-cleavage of APP remained unchanged. This is the first report that clarifies the regulatory mechanism of Presenilin 1/γ-secretase
with respect to its subcellular distribution and its differential substrate cleavage. Because the cleavage of various membrane
proteins by Presenilin 1/γ-cleavage is involved in cellular signaling, glycogen synthase kinase 3β-mediated phosphorylation
of Presenilin 1 should be deeply associated with signaling functions. Our findings indicate that the abnormal activation of
glycogen synthase kinase 3β can reduce neuronal viability and synaptic plasticity via modulating Presenilin 1/N-cadherin/β-catenin
interaction and thus have important implications in the pathophysiology of Alzheimer disease.
Journal of Biological Chemistry 05/2007; 282(21):15823-15832. · 4.77 Impact Factor
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[show abstract]
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ABSTRACT: One of the pathologic hallmarks of Alzheimer's disease is the excessive deposition of beta-amyloid peptides (Abeta) in senile plaques. Abeta is generated when beta-amyloid precursor protein (APP) is cleaved sequentially by beta-secretase, identified as beta-site APP-cleaving enzyme 1 (BACE1), and gamma-secretase, a putative enzymatic complex containing presenilin 1 (PS1). However, functional interaction between PS1 and BACE1 has never been known. In addition to this classical role in the generation of Abeta peptides, it has also been proposed that PS1 affects the intracellular trafficking and maturation of selected membrane proteins. We show that the levels of exogenous and endogenous mature BACE1 expressed in presenilin-deficient mouse embryonic fibroblasts (PS-/-MEFs) were reduced significantly compared to those in wild-type MEFs. Moreover, the levels of mature BACE1 were increased in human neuroblastoma cell line, SH-SY5Y, stably expressing wild-type PS1, compared to native cells. Conversely, the maturation of BACE1 was compromised under the stable expression of dominant-negative mutant PS1 overexpression. Immunoprecipitation assay showed that PS1 preferably interacts with proBACE1 rather than mature BACE1, indicating that PS1 can be directly involved in the maturation process of BACE1. Further, endogenous PS1 was immunoprecipitated with endogenous BACE1 in SH-SY5Y cells and mouse brain tissue. We conclude that PS1 is directly involved in the maturation of BACE1, thus possibly functioning as a regulator of both beta- and gamma-secretase in Abeta generation.
Journal of Neuroscience Research 02/2007; 85(1):153-65. · 2.74 Impact Factor
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[show abstract]
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ABSTRACT: N-cadherin is essential for excitatory synaptic contact in the hippocampus. At the sites of synaptic contact, it forms a complex with Presenilin 1(PS1) and beta-catenin. N-cadherin is cleaved by ADAM10 in response to NMDA receptor stimulation, producing a membrane fragment Ncad/CTF1 in neurons. NMDA receptor stimulation also enhances PS1/gamma-secretase-mediated cleavage of N-cadherin. To characterize the regulatory mechanisms of the ADAM10 and PS1-mediated cleavages, we first identified the precise cleavage sites of N-cadherin by ADAM10 and PS1/gamma-secretase by producing cleavage-deficient N-cadherin mutants. Next, we found that ectodomain shedding of N-cadherin by ADAM10 is a primary regulatory step in response to calcium influx, and that it is required for the subsequent PS1/gamma-secretase-mediated epsilon-cleavage of N-cadherin, which is a constitutive process to yield a cytoplasmic fragment, Ncad/CTF2. Since N-cadherin is essential for the structure and function of synapses including the long-term potentiation, those proteolytic events of N-cadherin should affect the adhesive behavior of the synapses, thereby taking part in learning and memory.
Neuroscience Letters 08/2006; 402(3):278-83. · 2.11 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: N-cadherin is essential for excitatory synaptic contact in the hippocampus. Presenilin 1 (PS1) is located at sites of synaptic contact, forming a complex with N-cadherin and beta-catenin. Here, we report that human N-cadherin is cleaved by PS1/gamma-secretase in response to physiological concentration of glutamate (Glu) stimulation, yielding a fragment Ncad/CTF2. The expression of Ncad/CTF2 in neuronal cells led to its translocation to the nucleus, and caused a prominent enhancement of cytoplasmic and nuclear beta-catenin levels in a cell-cell contact dependent manner, via following mechanisms: 1, inhibition of beta-catenin phosphorylation; 2, transactivation of beta-catenin; and 3, inhibition of N-cadherin transcription, and finally enhanced beta-catenin nuclear signaling. Since the regulation of cellular beta-catenin level is essential for synaptic function, disruption in the cleavage of N-cadherin may be causally linked to the synaptic dysfunction associated with Alzheimer's disease (AD).
Biochemical and Biophysical Research Communications 08/2006; 345(3):951-8. · 2.48 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Mutations in presenilin 1 (PS1) cause early-onset familial Alzheimer;s disease (FAD). Although FAD accounts for less than 5% of all cases of Alzheimer;s disease (AD), extensive analyses of PS1 function have elucidated an important neuronal mechanism underling AD pathogenesis. PS1 is considered to be an essential component of gamma-secretase, which cleaves amyloid precursor protein (APP) at the transmembrane region and releases amyloid beta (Abeta) peptide. In addition to this well-documented function, a growing amount of evidence suggests that PS1 is involved in the intracellular trafficking of selected membrane proteins (i.e. APP, nicastrin, trkB, telencephalin). Recently, we have also shown that PS1 is involved in the trafficking of N-cadherin from the endoplasmic reticulum to the plasma membrane via the microtubule network. N-cadherin is localized at the synaptic junctional complex, providing an adhesive force across the synaptic cleft, and the its regulation is crucial for the neuron to exert its specific function, i.e. synaptic activity. In a mature neuron, polarized targeting of proteins from the cell body to the axonal and dendritic processes is essential for its proper function, especially, for the maintenance of synaptic function. Alterations in protein transport caused by a dysfunction in PS1 could lead to a disturbance in synaptic transmission and finally to neurodegeneration. This article will review the current knowledge of PS1 function in protein trafficking and discuss its potential role in AD pathogenesis.
Current Alzheimer Research 03/2004; 1(1):1-10. · 3.95 Impact Factor
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[show abstract]
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ABSTRACT: One pathological characteristic of Alzheimer's disease (AD) is extensive synapse loss. Presenilin 1 (PS1) is linked to the pathogenesis of early onset familial Alzheimer's disease (FAD) and is localized at the synapse, where it binds N-cadherin and modulates its adhesive activity. To elucidate the role of the PS1/N-cadherin interaction in synaptic contact, we established SH-SY5Y cells stably expressing wild-type (wt) PS1 and dominant-negative (D385A) PS1. We show that the formation of cadherin-based cell-cell contact among SH-SY5Y cells stably expressing D385A PS1 was suppressed. Conversely, wt PS1 cells exhibited enhanced cell-cell contact and colony formation. Suppression of cell-cell contact in D385A cells was accompanied by an alteration in N-cadherin subcellular localization; N-cadherin was retained mainly in the endoplasmic reticulum (ER) and cell surface expression was reduced. We conclude that PS1 is essential for efficient trafficking of N-cadherin from the ER to the plasma membrane. PS1-mediated delivery of N-cadherin to the plasma membrane is important for N-cadherin to exert its physiological function, and it may control the state of cell-cell contact.
Journal of Neuroscience Research 11/2003; 74(2):184-91. · 2.74 Impact Factor
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[hide abstract]
ABSTRACT: Presenilin 1 interacts with beta-catenin, an essential component of the Wnt signaling pathway. To elucidate the role of presenilin 1-beta-catenin interaction in neuronal differentiation, we established SH-SY5Y cells stably expressing wild-type presenilin 1, P117L mutant presenilin 1, which is linked to the early-onset familial form of Alzheimer's disease, and D385A mutant presenilin 1, which has no aspartyl proteinase activity. We demonstrate that SH-SY5Y cells stably expressing D385A mutant presenilin 1 failed to differentiate in response to retinoic acid treatment. Retinoic acid caused an increase in nuclear beta-catenin levels in SH-SY5Y cells, which was followed by an increase in cyclin D1 protein levels. Abnormal cellular accumulation of beta-catenin was observed in D385A mutant transfected cells, whereas nuclear beta-catenin and cellular cyclin D1 levels failed to increase. Conversely, SH-SY5Y cells expressing the P117L mutant differentiated normally and showed increased nuclear beta-catenin and cellular cyclin D1 levels. These findings suggest that neuronal differentiation of SH-SY5Y cells involves the Wnt signaling pathway and that presenilin 1 plays a crucial role in Wnt signal transduction by regulating the nuclear translocation of beta-catenin.
Journal of Neuroscience Research 08/2003; 73(2):166-75. · 2.74 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Many cases of autosomal dominant early onset familial Alzheimer's disease result from mutations in presenilin-1 (PS1). In this study, we examined the role of the PS1 homologue gene sel-12 of Caenorhabditis elegans under oxidative stress and clarified the sel-12-induced apoptosis. A genetic null allele mutant, sel-12(ar171), showed resistance to oxidative stress and prevented mitochondrial dysfunction-induced apoptosis. On the other hand, another allele mutant, sel-12(ar131), that carries a missense mutation showed a proapoptotic activity, which may be the result of a gain of function property. Also, sel-12(ar131)-induced apoptosis was ced-3- and ced-4-dependent. Dantrolene, which specifically inhibits Ca(2+) release from endoplasmic reticulum stores, prevents sel-12(ar131)-induced apoptosis. SEL-12, which is localized in the endoplasmic reticulum, may induce apoptosis through abnormal calcium release from the endoplasmic reticulum. Together, with the previous finding that human PS1 could substitute for SEL-12, these results suggest the similar involvement of PS1-inducing apoptosis under oxidative stress and mitochondrial dysfunction in the Alzheimer's Disease brain.
Journal of Biological Chemistry 05/2003; 278(14):12130-4. · 4.77 Impact Factor
