title: Diaminothiazoles modify Tau phosphorylation and improve the tauopathy in mouse models.
abstract: Although Tau accumulation is a feature of several neurodegenerative conditions, treatment options for these conditions are nonexistent. Targeting Tau kinases represents a potential therapeutic approach. Small molecules in the diaminothiazole class are potent Tau kinase inhibitors that target CDK5 and GSK3β. Lead compounds from the series have IC50 values toward CDK5/p25 and GSK3β in the low nanomolar range and no observed toxicity in the therapeutic dose range. Neuronal protective effects and decreased PHF-1 immunoreactivity were observed in two animal models, 3×Tg-AD and CK-p25. Treatment nearly eliminated Sarkosyl-insoluble Tau with the most prominent effect on the phosphorylation at Ser-404. Treatment also induced the recovery of memory in a fear conditioning assay. Given the contribution of both CDK5/p25 and GSK3β to Tau phosphorylation, effective treatment of tauopathies may require dual kinase targeting.
authors.affiliation: Neuroscience Research Institute, Department of Molecular, Cellular, and Developmental Biology, University of California at Santa Barbara, Santa Barbara, California 93106, USA.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Zhang
authors.forename: Israel
authors.initials: I
authors.lastname: Hernandez
authors.forename: Damien
authors.initials: D
authors.lastname: Rei
authors.forename: Waltraud
authors.initials: W
authors.lastname: Mair
authors.forename: Joydev K
authors.initials: JK
authors.lastname: Laha
authors.forename: Madison E
authors.initials: ME
authors.lastname: Cornwell
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Cuny
authors.forename: Li-Huei
authors.initials: LH
authors.lastname: Tsai
authors.forename: Judith A J
authors.initials: JA
authors.lastname: Steen
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Kosik
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D003959:Diamines / Q000737:chemistry; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D007279:Injections, Subcutaneous; D007858:Learning / Q000187:drug effects; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects*; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D024801:Tauopathies / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D013844:Thiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D016896:Treatment Outcome; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D003959:Diamines; D018696:Neuroprotective Agents; D053764:Presenilin-1; D047428:Protein Kinase Inhibitors; D013844:Thiazoles; D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: Alzheimer Disease; CDK (Cyclin-dependent Kinase); Glycogen Synthase Kinase 3; Kinase Inhibitor; Neurodegenerative Diseases; Protein Phosphorylation; Tauopathy