c-Jun N-terminal kinases (JNKs) are a family of proteinkinasesactivated by a myriad of stimuli consequently modulating a vast rangeof biological processes. In human postmortem brain samples affectedwith Alzheimer ' s disease (AD), JNK overactivation has beendescribed; however, its role in AD onset and progression is stillunder debate. One of the earliest affected areas in the pathologyis the entorhinal cortex (EC). Noteworthy, the deterioration of theprojection from EC to hippocampus (Hp) point toward the idea thatthe connection between EC and Hp is lost in AD. Thus, the main objectiveof the present work is to address if JNK3 overexpression in the ECcould impact on the hippocampus, inducing cognitive deficits. Dataobtained in the present work suggest that JNK3 overexpression in theEC influences the Hp leading to cognitive impairment. Moreover, proinflammatorycytokine expression and Tau immunoreactivity were increased both inthe EC and in the Hp. Therefore, activation of inflammatory signalingand induction of Tau aberrant misfolding caused by JNK3 could be responsiblefor the observed cognitive impairment. Altogether, JNK3 overexpressionin the EC may impact on the Hp inducing cognitive dysfunction andunderlie the alterations observed in AD.