title: Hypothermia-induced hyperphosphorylation: a new model to study tau kinase inhibitors.
abstract: Tau hyperphosphorylation is one hallmark of Alzheimer's disease (AD) pathology. Pharmaceutical companies have thus developed kinase inhibitors aiming to reduce tau hyperphosphorylation. One obstacle in screening for tau kinase inhibitors is the low phosphorylation levels of AD-related phospho-epitopes in normal adult mice and cultured cells. We have shown that hypothermia induces tau hyperphosphorylation in vitro and in vivo. Here, we hypothesized that hypothermia could be used to assess tau kinase inhibitors efficacy. Hypothermia applied to models of biological gradual complexity such as neuronal-like cells, ex vivo brain slices and adult non-transgenic mice leads to tau hyperphosphorylation at multiple AD-related phospho-epitopes. We show that Glycogen Synthase Kinase-3 inhibitors LiCl and AR-A014418, as well as roscovitine, a cyclin-dependent kinase 5 inhibitor, decrease hypothermia-induced tau hyperphosphorylation, leading to different tau phosphorylation profiles. Therefore, we propose hypothermia-induced hyperphosphorylation as a reliable, fast, convenient and inexpensive tool to screen for tau kinase inhibitors.
authors: Université Laval, Faculté de Médecine, Département de Neurosciences et Psychiatrie.
authors: Alexis
authors: A
authors: Bretteville
authors: François
authors: F
authors: Marcouiller
authors: Carl
authors: C
authors: Julien
authors: Noura B
authors: NB
authors: El Khoury
authors: Franck R
authors: FR
authors: Petry
authors: Isabelle
authors: I
authors: Poitras
authors: Didier
authors: D
authors: Mouginot
authors: Georges
authors: G
authors: Lévesque
authors: Sébastien S
authors: SS
authors: Hébert
authors: Emmanuel
authors: E
authors: Planel
mesh_terms: D000758:Anesthesia; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007035:Hypothermia / Q000139:chemically induced / Q000201:enzymology; D018021:Lithium Chloride / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D051360:Cyclin-Dependent Kinase 5; D038362:Glycogen Synthase Kinase 3; C080888:tau-protein kinase; D018021:Lithium Chloride