Interplay between cyclin-dependent kinase 5 and glycogen synthase kinase 3 beta mediated by neuregulin signaling leads to differential effects on tau phosphorylation and amyloid precursor protein processing.
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.
Wen
Yi
Y
Taub Institute at Columbia University Medical Center, New York State Psychiatric Institute, New York, New York 10032, USA.
Planel
Emmanuel
E
Herman
Mathieu
M
Figueroa
Helen Y
HY
Wang
Lili
L
Liu
Li
L
Lau
Lit-Fui
LF
Yu
Wai Haung
WH
Duff
Karen E
KE
D000367:Age Factors; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000502:physiology; D020880:Neuregulins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018739:Oncogene Proteins v-erbB / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation; D010770:Phosphotransferases; D025941:Protein Interaction Mapping; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; C492236:Cdk5r1 protein, mouse; D009419:Nerve Tissue Proteins; D020880:Neuregulins; D018739:Oncogene Proteins v-erbB; D047428:Protein Kinase Inhibitors; D016875:tau Proteins; D010770:Phosphotransferases; D019869:Phosphatidylinositol 3-Kinases; D051360:Cyclin-Dependent Kinase 5; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3