title: Cyclin-Dependent kinase 5 targeting prevents β-Amyloid aggregation involving glycogen synthase kinase 3β and phosphatases.
abstract: Inappropriate activation of cyclin-dependent kinase 5 (CDK5) resulting from proteolytic release of the activator fragment p25 from the membrane contributes to the formation of neurofibrillary tangles, β-amyloid (βA) aggregation, and chronic neurodegeneration. At 18 months of age, 3× Tg-AD mice were sacrificed after either 3 weeks (short term) or 1 year (long term) of CDK5 knockdown. In short-term-treated animals, CDK5 knockdown reversed βA aggregation in the hippocampi via inhibitory phosphorylation of glycogen synthase kinase 3β Ser9 and activation of phosphatase PP2A. In long-term-treated animals, CDK5 knockdown induced a persistent reduction in CDK5 and prevented βA aggregation, but the effect on amyloid precursor protein processing was reduced, suggesting that yearly booster therapy would be required. These findings further validate CDK5 as a target for preventing or blocking amyloidosis in older transgenic mice.
authors.affiliation: Cellular and Molecular Neurobiology Area, Neuroscience Group of Antioquia, Faculty of Medicine, SIU, University of Antioquia, Medellín, Colombia.
authors.forename: John Fredy
authors.initials: JF
authors.lastname: Castro-Alvarez
authors.affiliation: Cellular and Molecular Neurobiology Area, Neuroscience Group of Antioquia, Faculty of Medicine, SIU, University of Antioquia, Medellín, Colombia.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Uribe-Arias
authors.affiliation: Cellular and Molecular Neurobiology Area, Neuroscience Group of Antioquia, Faculty of Medicine, SIU, University of Antioquia, Medellín, Colombia.
authors.forename: Gloria Patricia
authors.initials: GP
authors.lastname: Cardona-Gómez
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018390:Gene Targeting / Q000379:methods*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D051379:Mice; D008822:Mice, Transgenic; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D016229:Amyloid beta-Peptides; D051360:Cyclin-Dependent Kinase 5; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C495906:Cdk5 protein, mouse; D038362:Glycogen Synthase Kinase 3; D010744:Phosphoric Monoester Hydrolases
keywords: Alzheimer's disease; CDK5 RNAi; GSK3β Ser9; PP2A; β-amyloid plaques