p35/Cyclin-dependent kinase 5 is required for protection against beta-amyloid-induced cell death but not tau phosphorylation by ceramide.
Ceramide is a bioactive sphingolipid that can prevent calpain activation and beta-amyloid (A beta) neurotoxicity in cortical neurons. Recent evidence supports A beta induction of a calpain-dependent cleavage of the cyclin-dependent kinase 5 (cdk5) regulatory protein p35 that contributes to tau hyperphosphorylation and neuronal death. Using cortical neurons isolated from wild-type and p35 knockout mice, we investigated whether ceramide required p35/cdk5 to protect against A beta-induced cell death and tau phosphorylation. Ceramide inhibited A beta-induced calpain activation and cdk5 activity in wild-type neurons and protected against neuronal death and tau hyperphosphorylation. Interestingly, A beta also increased cdk5 activity in p35-/- neurons, suggesting that the alternate cdk5 regulatory protein, p39, might mediate this effect. In p35 null neurons, ceramide blocked A beta-induced calpain activation but did not inhibit cdk5 activity or cell death. However, ceramide blocked tau hyperphosphorylation potentially via inhibition of glycogen synthase kinase-3beta. These data suggest that ceramide can regulate A beta cell toxicity in a p35/cdk5-dependent manner.
Seyb
Kathleen I
KI
Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS 66045, USA.
Ansar
Sabah
S
Li
Guibin
G
Bean
Jennifer
J
Michaelis
Mary L
ML
Dobrowsky
Rick T
RT
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002154:Calpain / Q000378:metabolism; D016923:Cell Death / Q000502:physiology*; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism*; D002540:Cerebral Cortex / Q000166:cytology; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D002518:Ceramides; D009419:Nerve Tissue Proteins; C089495:neuronal Cdk5 activator (p25-p35); D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D002154:Calpain