p35/Cdk5 pathway mediates soluble amyloid-beta peptide-induced tau phosphorylation in vitro.
Alzheimer's disease (AD) is pathologically characterized by deposition of amyloid-beta peptides (Abeta) as senile plaques and by the occurrence of neurofibrillary tangles (NFTs) composed primarily of hyperphosphorylated tau protein. Activation of cyclin-dependent kinase 5 (Cdk5) via its potent activator p25 has recently been shown to promote phosphorylation of tau at AD-specific phosphoepitopes, and increased cleavage of p35 to p25 has been demonstrated in AD patients, suggesting that Cdk5 may represent a pathogenic tau protein kinase. We were interested in the potential effect of soluble forms of Abeta on Cdk5-mediated AD-like tau phosphorylation, insofar as previous studies of human biopsies and aged canine and primate brains have shown that dystrophic neurites appear before the formation of neuritic plaques. We transfected N2a cells with a p35 vector (N2a/p35 cells) and, after differentiation, challenged these cells with Abeta(1-42) peptide in soluble form (sAbeta(1-42)). Results show that sAbeta(1-42) at relatively low levels (1-5 microM) dose-dependently increases tau phosphorylation at AD-specific phosphoepitopes in differentiated N2a/p35 cells compared with controls, an effect that is blocked by antisense oligonucleotides against p35. sAbeta(1-42)-induced tau phosphorylation is concomitant with an increase in both p25 to p35 ratio and Cdk5 activity (but not protein levels). Additionally, blockade of L-type calcium channels or inhibition of calpain completely abolishes this effect. Taken together, these data indicate that sAbeta is a potent activator of the p25/Cdk5 pathway, resulting in promotion of AD-like tau phosphorylation in vitro.
Town
Terrence
T
The Roskamp Institute, Department of Psychiatry, University of South Florida, Tampa 33613, USA.
Zolton
Joseph
J
Shaffner
Reed
R
Schnell
Billy
B
Crescentini
Robert
R
Wu
Yajuan
Y
Zeng
Jin
J
DelleDonne
Anthony
A
Obregon
Demian
D
Tan
Jun
J
Mullan
Mike
M
D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D018929:Cell Culture Techniques; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005822:Genetic Vectors; D006801:Humans; D007150:Immunohistochemistry; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects; D016875:tau Proteins / Q000187:drug effects / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D020746:Calcium Channels, L-Type; D009419:Nerve Tissue Proteins; C089495:neuronal Cdk5 activator (p25-p35); D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; D018844:Cyclin-Dependent Kinases; D002154:Calpain