Glucocorticoids trigger Alzheimer disease-like pathobiochemistry in rat neuronal cells expressing human tau.
Amyloid precursor protein (APP) mis-processing and aberrant tau hyperphosphorylation are causally related to the pathogenesis and neurodegenerative processes that characterize Alzheimer's disease (AD). Abnormal APP metabolism leads to the generation of neurotoxic amyloid beta (Abeta), whereas tau hyperphosphorylation culminates in cytoskeletal disturbances, neuronal dysfunction and death. Many AD patients hypersecrete glucocorticoids (GC) while neuronal structure, function and survival are adversely influenced by elevated GC levels. We report here that a rat neuronal cell line (PC12) engineered to express the human ortholog of the tau protein (PC12-htau) becomes more vulnerable to the toxic effects of either Abeta or GC treatment. Importantly, APP metabolism in GC-treated PC12-htau cells is selectively shifted towards increased production of the pro-amyloidogenic peptide C99. Further, GC treatment results in hyperphosphorylation of human tau at AD-relevant sites, through the cyclin-dependent kinase 5 (E.C. 2.7.11.26) and GSK3 (E.C. 2.7.11.22) protein kinases. Pulse-chase experiments revealed that GC treatment increased the stability of tau protein rather than its de novo synthesis. GC treatment also induced accumulation of transiently expressed EGFP-tau in the neuronal perikarya. Together with previous evidence showing that Abeta can activate cyclin-dependent kinase 5 and GSK3, these results uncover a potential mechanism through which GC may contribute to AD neuropathology.
Sotiropoulos
Ioannis
I
NeuroAdaptations Group, Max Planck Institute of Psychiatry, Munich, Germany.
Catania
Caterina
C
Riedemann
Therese
T
Fry
Jonathan P
JP
Breen
Kieran C
KC
Michaelidis
Theologos M
TM
Almeida
Osborne F X
OF
D016229:Amyloid beta-Peptides / Q000633:toxicity; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D056849:Cyclin-Dependent Kinase 3; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D006801:Humans; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D016716:PC12 Cells / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013778:Tetrazolium Salts; D013844:Thiazoles; D014162:Transfection; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D013778:Tetrazolium Salts; D013844:Thiazoles; D016875:tau Proteins; D049452:Green Fluorescent Proteins; D003907:Dexamethasone; D051360:Cyclin-Dependent Kinase 5; C098776:CDK3 protein, human; D056849:Cyclin-Dependent Kinase 3; D018844:Cyclin-Dependent Kinases; C022616:thiazolyl blue