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The Journal of Neuroscience, March 5, 2008, 28(10):2624-2632; doi:10.1523/JNEUROSCI.5245-07.2008

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Cellular/Molecular
Interplay between Cyclin-Dependent Kinase 5 and Glycogen Synthase Kinase 3β Mediated by Neuregulin Signaling Leads to Differential Effects on Tau Phosphorylation and Amyloid Precursor Protein Processing

Yi Wen,¹ Emmanuel Planel,¹ Mathieu Herman,¹ Helen Y. Figueroa,¹ Lili Wang,¹ Li Liu,¹ Lit-Fui Lau,² Wai Haung Yu,¹ and Karen E. Duff¹

¹Taub Institute at Columbia University Medical Center, New York State Psychiatric Institute, New York, New York 10032, and ²CNS Discovery, Pfizer Global Research and Development, Groton, Connecticut 06340

Correspondence should be addressed to Karen E. Duff, Taub Institute for Alzheimer's Disease Research, Columbia University Medical Center, 650 West 168th Street, BB-513, New York, NY 10032. Email: ked2115{at}columbia.edu

Cyclin-dependent kinase 5 (cdk5) and glycogen synthase kinase 3β (GSK3β) 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 β (Aβ) production. Here we show that young p25 overexpressing mice have enhanced cdk5 activity but reduced GSK3β activity attributable to phosphorylation at the inhibitory GSK3β–serine 9 (GSK3β–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 Aβ 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 GSK3β plays a dominant role in overall tau phosphorylation. In older mice, GSK3β inhibitory phosphorylation at S9 was reduced relative to young mice. Aβ peptide levels were still elevated but phospho-tau levels were either unchanged or showed a trend to increase, suggesting that GSK3β activity increases with aging. Inhibition of cdk5 by a specific inhibitor reduced cdk5 activity in p25 mice, leading to reduced Aβ production in both young and old mice. However, in young mice, cdk5 inhibition reversed GSK3β inhibition, leading to an increase in overall tau phosphorylation. When cdk5 inhibitor was administered to very old, nontransgenic mice, inhibition of cdk5 reduced Aβ levels, and phospho-tau levels showed a trend to increase. Thus, cdk5 inhibitors may not be effective in targeting tau phosphorylation in the elderly.

Key words: Alzheimer's disease; tau; cdk5; GSK3β; neuregulin receptors; APP; Aβ

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Received July 13, 2007; accepted Jan. 13, 2008.

Correspondence should be addressed to Karen E. Duff, Taub Institute for Alzheimer's Disease Research, Columbia University Medical Center, 650 West 168th Street, BB-513, New York, NY 10032. Email: ked2115{at}columbia.edu

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