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.
Keywords:
Alzheimer Disease; CDK (Cyclin-dependent Kinase); Glycogen Synthase Kinase 3; Kinase Inhibitor; Neurodegenerative Diseases; Protein Phosphorylation; Tauopathy.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Alzheimer Disease / genetics
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Alzheimer Disease / metabolism
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Alzheimer Disease / prevention & control
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Amyloid beta-Peptides / genetics
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Amyloid beta-Peptides / metabolism
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Animals
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Blotting, Western
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Cyclin-Dependent Kinase 5 / antagonists & inhibitors
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Cyclin-Dependent Kinase 5 / genetics
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Cyclin-Dependent Kinase 5 / metabolism
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Diamines / chemistry
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Disease Models, Animal*
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Glycogen Synthase Kinase 3 / antagonists & inhibitors
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Glycogen Synthase Kinase 3 beta
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Humans
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Injections, Intraperitoneal
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Injections, Intraventricular
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Injections, Subcutaneous
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Learning / drug effects
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Male
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Memory / drug effects
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Mice
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Mice, Transgenic
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / pharmacokinetics
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Neuroprotective Agents / pharmacology
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Phosphorylation / drug effects*
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Presenilin-1 / genetics
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Presenilin-1 / metabolism
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology
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Tauopathies / genetics
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Tauopathies / metabolism
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Tauopathies / prevention & control*
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Thiazoles / administration & dosage
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Thiazoles / chemistry
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Thiazoles / pharmacokinetics
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Thiazoles / pharmacology*
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Treatment Outcome
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tau Proteins / genetics
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tau Proteins / metabolism*
Substances
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Amyloid beta-Peptides
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Diamines
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Neuroprotective Agents
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Presenilin-1
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Protein Kinase Inhibitors
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Thiazoles
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tau Proteins
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Cyclin-Dependent Kinase 5
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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Glycogen Synthase Kinase 3