Alzheimer's disease (AD) is characterized by an early hippocampus hyperactivity triggered by Aβ oligomers (Aβo) in humans and AD mouse models, followed by hypoactivity and synaptic loss occurring before cognitive decline. GWAS identified PTK2B gene encoding for Pyk2, a tyrosine kinase involved in synaptic plasticity, as a new AD risk factor. Several studies have validated Pyk2 involvement in AD pathophysiology, but its exact role is still debated due to conflicting results. The objective of this project is to decipher the role of Pyk2 in synaptic dysfunctions observed in this disease. We first showed by immunoblot that Aβo induce Pyk2 activation in synapses in primary neurons treated with Aβo and in the hippocampus of an AD transgenic mouse model. Patch-clamp experiments in hippocampal slices of Pyk2 KO mice treated with Aβo revealed Pyk2 involvement in hippocampal hyperactivity. Furthermore, we showed that overexpression of Pyk2 in cultured cortical neurons leads to a decrease in synaptic density independently of its activation or kinase activity. This alteration seems to involve protein interactions such as Tau that has been previously shown to be a potential substrate for Pyk2. Western blot analysis of Pyk2 KO mice hippocampus and transfection of primary neuronal culture highlighted that Pyk2 interacts with Tau and induces its localization and phosphorylation in the postsynaptic compartment. In summary, Pyk2 seems to be involved in the synaptic alterations observed in the early phases of AD at the interface of amyloid and Tau pathologies.