p120-catenin is necessary for neuroprotection induced by CDK5 silencing in models of Alzheimer's disease.
Cyclin-dependent kinase 5 (CDK5) plays important roles in synaptic function. Its unregulated over-activation has been, however, associated with neurodegeneration in Alzheimer's disease. Our previous studies revealed that CDK5 silencing ameliorates tauopathy and spatial memory impairment in the 3xTgAD mouse model. However, how CDK5 targeting affects synaptic adhesion proteins, such as those involved in the cadherin/catenin system, during learning and memory processes is not completely understood. In this study, we detected reduced expression of p120 catenin (p120 ctn), N-cadherin, and β-catenin in the brain of human Alzheimer's disease patients, in addition to a reduced PSD95 and GluN2B protein levels in a 3xTgAD mouse model. Such decrease in synaptic proteins was recovered by CDK5 silencing in mice leading to a better learning and memory performance. Additionally, CDK5 inhibition or knockout increased p120 ctn levels. Moreover, in a glutamate-induced excitotoxicity model, CDK5 silencing-induced neuroprotection depended on p120 ctn. Together, those findings suggest that p120 ctn plays an important role in the neuronal dysfunction of Alzheimer's disease models and contributes to CDK5 silencing-induced neuroprotection and improvement of memory function. p120ctn is part of the synaptic adhesion molecular complex N-cadh/p120ctn/B-ctn/PSD95, and it has a pivotal role in cell adhesion stabilization and dendritic spine modulation. Our data show that synaptic adhesion complex is affected in AD human brains and in AD models. This complex is recovered by the silencing of CDK5, preventing memory dysfunction in an AD mice model and contributing to the neuroprotection in a depend-mode of p120ctn.
Neuroscience Group of Antioquia, Faculty of Medicine, University of Antioquia, Medellín, Colombia.
Alejandro
A
Uribe-Arias
Neuroscience Group of Antioquia, Faculty of Medicine, University of Antioquia, Medellín, Colombia.
Rafael Andrés
RA
Posada-Duque
Laboratory of Cell and Neuronal Dynamics, Department of Biology Faculty of Sciences, Universidad de Chile, Ñuñoa, Santiago, Chile.|Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.
Christian
0000-0003-0335-1482
C
González-Billault
Neuroscience Group of Antioquia, Faculty of Medicine, University of Antioquia, Medellín, Colombia.
Andrés
A
Villegas
Neuroscience Group of Antioquia, Faculty of Medicine, University of Antioquia, Medellín, Colombia.
Francisco
F
Lopera
Neuroscience Group of Antioquia, Faculty of Medicine, University of Antioquia, Medellín, Colombia.
Gloria Patricia
GP
Cardona-Gómez
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D051177:Catenins / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D000066829:Neuroprotection / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism; D000095002:Delta Catenin
D015820:Cadherins; D051177:Catenins; D015815:Cell Adhesion Molecules; D010750:Phosphoproteins; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; C495906:Cdk5 protein, mouse; D000095002:Delta Catenin
Alzheimer's disease; CDK5; cadherin/catenin system; cognitive function; p120 ctn