Activation of neuronal extracellular receptor kinase (ERK) in Alzheimer disease links oxidative stress to abnormal phosphorylation

Perry, George; Roder, Hanno M.; Nunomura, Akihiko; Takeda, Atsushi; Friedlich, Allan L.; Zhu, Xiongwei; Raina, Arun K.; Holbrook, Nikki J.; Siedlak, Sandra L.; Harris, Peggy L.R.; Smith, Mark A.

doi:10.1097/00001756-199908020-00035

Cited by 271 publications

(192 citation statements)

References 5 publications

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“…However, sustained ERK1/2 activation has been associated with neuronal death (Alessandrini et al, 1999;Murray et al, 1998;Runden et al, 1998). Abnormal activation of the ERK1/2 pathway has also been implicated in the pathogenesis of Alzheimer's disease (Alessandrini et al, 1999;Drewes et al, 1992;Knowles et al, 1999;Perry et al, 1999;Trojanowski et al, 1993;Veeranna et al, 1998). In our studies, the level of activated and total ERK1/2 was increased but there was no evidence supporting a negative effect of the elevated levels on the hippocampal cultures.…”

Section: Discussioncontrasting

confidence: 59%

Chronic CXCL10 alters the level of activated ERK1/2 and transcriptional factors CREB and NF-κB in hippocampal neuronal cell culture

Bajova

Nelson

Gruol

2008

Journal of Neuroimmunology

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Signal transduction pathways may be important targets of chemokines during neuroinflammation. In the current study, Western blot analyses show that in rat hippocampal neuronal/glial cell cultures chronic CXCL10 increases the level of protein for ERK1/2 as well as for the transcriptional factors CREB and NF-κB. Bcl-2, an anti-apoptotic protein whose expression can be regulated by a pathway involving ERK1/2, CREB and NF-κB, was also increased in the CXCL10 treated cultures. These results implicate a role for ERK1/2, CREB and NF-κB in effects of CXCL10 on hippocampal cells and suggest that chronic CXCL10 may have a protective role during certain neuroinflammatory conditions.

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Section: Discussioncontrasting

confidence: 59%

Chronic CXCL10 alters the level of activated ERK1/2 and transcriptional factors CREB and NF-κB in hippocampal neuronal cell culture

Bajova

Nelson

Gruol

2008

Journal of Neuroimmunology

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“…Consequently even disease-specific tau phosphoepitopes, such as those related to certain Ser-422 phosphorylation-dependent epitopes (14), are fully reconstituted in vitro by ERK2, but not by other known tau-kinases like cdk5 or GSK3, which phosphorylate tau only to lower stoichiometric ratios. The finding that activated forms of ERK1 and ERK2 colocalize with the neurofibrillary lesions in postmortem AD brains (15,16) also is compatible with a role for ERKs in the pathological hyperphosphorylation of tau.…”

supporting

confidence: 60%

An inhibitor of tau hyperphosphorylation prevents severe motor impairments in tau transgenic mice

Corre¹,

Klafki²,

Plesnila

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

206

149

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An orally bioavailable and blood-brain barrier penetrating analog of the kinase inhibitor K252a was able to prevent the typical motor deficits in the tau (P301L) transgenic mouse model (JNPL3) and markedly reduce soluble aggregated hyperphosphorylated tau. However, neurofibrillary tangle counts were not reduced in the successfully treated cohort, suggesting that the main cytotoxic effects of tau are not exerted by neurofibrillary tangles but by lower molecular mass aggregates of tau. Our findings strongly suggest that abnormal tau hyperphosphorylation plays a critical role in the development of tauopathy and suggest a previously undescribed treatment strategy for neurodegenerative diseases involving tau pathology.Alzheimer's disease ͉ extracellular signal-regulated kinase inhibitor ͉ paired helical filament ͉ tangles

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“…Other changes of AD could very well be linked to mitochondria because blockage of mitochondrial energy production shifts amyloid ␤-protein precursor metabolism to the production of more amyloidgenic forms of amyloid-␤ (Gabuzda et al, 1994), induces the production of A68 antigen (Blass et al, 1990), and activates the mitogen-activated protein kinase pathway (Luo et al, 1997;Perry et al, 1999;Zhu et al, 2000Zhu et al, , 2001, all features of AD.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Abnormalities in Alzheimer's Disease

Aliev²,

et al. 2001

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The finding that oxidative damage, including that to nucleic acids, in Alzheimer's disease is primarily limited to the cytoplasm of susceptible neuronal populations suggests that mitochondrial abnormalities might be part of the spectrum of chronic oxidative stress of Alzheimer's disease. In this study, we usedin situhybridization to mitochondrial DNA (mtDNA), immunocytochemistry of cytochrome oxidase, and morphometry of electron micrographs of biopsy specimens to determine whether there are mitochondrial abnormalities in Alzheimer's disease and their relationship to oxidative damage marked by 8-hydroxyguanosine and nitrotyrosine. We found that the same neurons showing increased oxidative damage in Alzheimer's disease have a striking and significant increase in mtDNA and cytochrome oxidase. Surprisingly, much of the mtDNA and cytochrome oxidase is found in the neuronal cytoplasm and in the case of mtDNA, the vacuoles associated with lipofuscin. Morphometric analysis showed that mitochondria are significantly reduced in Alzheimer's disease. The relationship shown here between the site and extent of mitochondrial abnormalities and oxidative damage suggests an intimate and early association between these features in Alzheimer's disease.

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Activation of neuronal extracellular receptor kinase (ERK) in Alzheimer disease links oxidative stress to abnormal phosphorylation

Cited by 271 publications

References 5 publications

Chronic CXCL10 alters the level of activated ERK1/2 and transcriptional factors CREB and NF-κB in hippocampal neuronal cell culture

Chronic CXCL10 alters the level of activated ERK1/2 and transcriptional factors CREB and NF-κB in hippocampal neuronal cell culture

An inhibitor of tau hyperphosphorylation prevents severe motor impairments in tau transgenic mice

Mitochondrial Abnormalities in Alzheimer's Disease

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