GSK3β Activity Modifies the Localization and Function of Presenilin 1

Uemura, Kazunori; Kuzuya, Akira; Shimozono, Yoshiharu; Aoyagi, Nobuhisa; Andō, Kōichi; Shimohama, Shun; Kinoshita, Ayae

doi:10.1074/jbc.m610708200

Cited by 96 publications

(85 citation statements)

References 37 publications

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“…Interestingly, our kinetic analysis reveals that PS1 becomes necessary for maintaining PI3K signaling during this developmental stage, suggesting that PS1 may be necessary for contact-dependent activation of neuronal PI3K/Akt signaling. This suggestion is supported by recent data that PS1 regulates the cadherindependent activation of PI3K (Baki et al, 2004;Uemura et al, 2007).…”

Section: Discussionsupporting

confidence: 76%

“…Presenilin1 (PS1) is a ubiquitously expressed transmembrane protein that plays critical roles in development (Shen et al, 1997;Wong et al, 1997) and in early onset familial Alzheimer's disease (FAD) (Sherrington et al, 1995). Recent studies in fibroblast cells implicate PS1 in the regulation of the PI3K/Akt signaling pathway (Baki et al, 2004;Kang et al, 2005;Uemura et al, 2007). Here we used primary neuronal cultures to investigate the role of PS1 and its FAD mutants in the neuronal PI3K signaling, as such studies may yield information on the mechanism by which PS1 FAD mutations promote neurodegeneration.…”

Section: Introductionmentioning

confidence: 99%

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Wild-Type But Not FAD Mutant Presenilin-1 Prevents Neuronal Degeneration by Promoting Phosphatidylinositol 3-Kinase Neuroprotective Signaling

Baki

Neve²,

Shao³

et al. 2008

J. Neurosci.

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The role of presenilin-1 (PS1) in neuronal phosphatidylinositol 3-kinase (PI3K)/Akt signaling was investigated in primary neuronal cultures from wild-type (WT) and PS1 null (PS1؊/؊) embryonic mouse brains. Here we show that in PS1Ϫ/Ϫ cultures, the onset of neuronal maturation coincides with a decrease in the PI3K-dependent phosphorylation-activation of Akt and phosphorylationinactivation of glycogen synthase kinase-3 (GSK-3). Mature PS1Ϫ/Ϫ neurons show increased activation of apoptotic caspase-3 and progressive degeneration preceded by dendritic retraction. Expression of exogenous WT PS1 or constitutively active Akt in PS1Ϫ/Ϫ neurons stimulates PI3K signaling and suppresses both caspase-3 activity and dendrite retraction. The survival effects of PS1 are sensitive to inhibitors of PI3K kinase but insensitive to ␥-secretase inhibitors. Familial Alzheimer disease (FAD) mutations suppress the ability of PS1 to promote PI3K/AKT signaling, prevent phosphorylation/inactivation of GSK-3 and promote activation of caspase-3. These mutation effects are reversed upon coexpression of constitutively active Akt. Together, our data indicate that the neuroprotective role of PS1 depends on its ability to activate the PI3K/Akt signaling pathway and that PS1 FAD mutations increase GSK-3 activity and promote neuronal apoptosis by inhibiting the function of PS1 in this pathway. These observations suggest that stimulation of PI3K/Akt signaling may be beneficial to FAD patients.

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Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Wild-Type But Not FAD Mutant Presenilin-1 Prevents Neuronal Degeneration by Promoting Phosphatidylinositol 3-Kinase Neuroprotective Signaling

Baki

Neve²,

Shao³

et al. 2008

J. Neurosci.

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“…HA-tagged MEKK3 (Addgene plasmid 12186) was provided by Dr. Johnson (National Jewish Center for Immunology and Respiratory Medicine) (23). HA-tagged N-cadherin was described elsewhere (14). Transfection of either HEK293 or COS7 cells was carried out using Transfectin reagent (BioRad) according to the manufacturer's protocol.…”

Section: Methodsmentioning

confidence: 99%

mentioning

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.…”

mentioning

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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The emerging nontraditional roles for tau in the brain

Tseng,

Cohen

2023

Cytoskeleton

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GSK3β Activity Modifies the Localization and Function of Presenilin 1

Cited by 96 publications

References 37 publications

Wild-Type But Not FAD Mutant Presenilin-1 Prevents Neuronal Degeneration by Promoting Phosphatidylinositol 3-Kinase Neuroprotective Signaling

Wild-Type But Not FAD Mutant Presenilin-1 Prevents Neuronal Degeneration by Promoting Phosphatidylinositol 3-Kinase Neuroprotective Signaling

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

The emerging nontraditional roles for tau in the brain

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