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 -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. ; Departamento Administrativo de Ciencia, Tecnologia e Innovacion, Mobility's Project Colombia-Chile, PROLAB Collaboration in Latin America/IBRO, Fogarty International Center, NIA of NIH, CONICYT, FONDAP