Cyclin-Dependent kinase 5 targeting prevents beta-Amyloid aggregation involving glycogen synthase kinase 3 beta and phosphatases

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, -amyloid (A) aggregation, and chronic neurodegeneration. At 18 months of age, 3x 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 A aggregation in the hippocampi via inhibitory phosphorylation of glycogen synthase kinase 3 Ser9 and activation of phosphatase PP2A. In long-term-treated animals, CDK5 knockdown induced a persistent reduction in CDK5 and prevented A 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. (c) 2015 Wiley Periodicals, Inc.