Interplay between cyclin-dependent kinase 5 and glycogen synthase kinase 3beta mediated by neuregulin signaling leads to differential effects on tau phosphorylation and amyloid precursor protein processing.

Interplay between cyclin-dependent kinase 5 and glycogen synthase kinase 3beta mediated by neuregulin signaling leads to differential effects on tau phosphorylation and amyloid precursor protein processing. Research Abstract Details 

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Interplay between cyclin-dependent kinase 5 and glycogen synthase kinase 3beta mediated by neuregulin signaling leads to differential effects on tau phosphorylation and amyloid precursor protein processing. Abstract Text:

Yi Wen,Emmanuel Planel,Mathieu Herman,Helen Y Figueroa,Lili Wang,Li Liu,Lit-Fui Lau,Wai Haung Yu,Karen E Duff,

Cyclin-dependent kinase 5 (cdk5) and glycogen synthase kinase 3beta (GSK3beta) have been implicated in pathogenic processes associated with Alzheimer's disease because both kinases regulate tau hyperphosphorylation and enhance amyloid precursor protein (APP) processing leading to an increase in amyloid beta (Abeta) production. Here we show that young p25 overexpressing mice have enhanced cdk5 activity but reduced GSK3beta activity attributable to phosphorylation at the inhibitory GSK3beta-serine 9 (GSK3beta-S9) site. Phosphorylation at this site was mediated by enhanced activity of the neuregulin receptor complex, ErbB, and activation of the downstream phosphatidylinositol 3 kinase/Akt pathway. Young p25 mice had elevated Abeta peptide levels, but phospho-tau levels were decreased overall. Thus, cdk5 appears to play a dominant role in the regulation of amyloidogenic APP processing, whereas GSK3beta plays a dominant role in overall tau phosphorylation. In older mice, GSK3beta inhibitory phosphorylation at S9 was reduced relative to young mice. Abeta peptide levels were still elevated but phospho-tau levels were either unchanged or showed a trend to increase, suggesting that GSK3beta activity increases with aging. Inhibition of cdk5 by a specific inhibitor reduced cdk5 activity in p25 mice, leading to reduced Abeta production in both young and old mice. However, in young mice, cdk5 inhibition reversed GSK3beta inhibition, leading to an increase in overall tau phosphorylation. When cdk5 inhibitor was administered to very old, nontransgenic mice, inhibition of cdk5 reduced Abeta levels, and phospho-tau levels showed a trend to increase. Thus, cdk5 inhibitors may not be effective in targeting tau phosphorylation in the elderly.

Interplay between cyclin-dependent kinase 5 and glycogen synthase kinase 3beta mediated by neuregulin signaling leads to differential effects on tau phosphorylation and amyloid precursor protein processing. Publishing Authors By Initials

Y Wen,E Planel,M Herman,HY Figueroa,L Wang,L Liu,LF Lau,WH Yu,KE Duff,

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Interplay between cyclin-dependent kinase 5 and glycogen synthase kinase 3beta mediated by neuregulin signaling leads to differential effects on tau phosphorylation and amyloid precursor protein processing. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: The Journal of neuroscience : the official journal

VOLUME: 28

Page Numbers: 2624-32

Journal Abbreviation: J. Neurosci.

ISSN: 1529-2401

DAY: 5

MONTH: Mar

YEAR: 2008

Interplay between cyclin-dependent kinase 5 and glycogen synthase kinase 3beta mediated by neuregulin signaling leads to differential effects on tau phosphorylation and amyloid precursor protein processing. Information

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LANGUAGE: eng

NlmUniqueID: 8102140

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Grant and Affiliation Information for Interplay between cyclin-dependent kinase 5 and glycogen synthase kinase 3beta mediated by neuregulin signaling leads to differential effects on tau phosphorylation and amyloid precursor protein processing.

AFFILIATION: Taub Institute at Columbia University Medical Center, New York State Psychiatric Institute, New York, New York 10032, USA.

Country: United States

AGENCY: United States NINDS

GRANT: NS48447

ACRONYM: NS

MEDLINETA: J Neurosci

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