Growing evidences demonstrate that chemokines and chemokine receptors are up-regulated in resident central nervous system cells during Alzheimer's disease contributing to neuroinflammation and neurodegeneration. Prokineticin 2 belongs to a new family of chemokines which recently emerged as a critical player in immune system and inflammatory diseases. Since pharmacological blockade in vitro of the prokineticin system is able to antagonize Amyloid β-induced neurotoxicity, the aim of the present study was to investigate in vivo effects of prokineticin receptor antagonist PC1 on memory impairment in a rodent model of Alzheimer's disease. Rats were intracerebroventricular infused with Aβ1-42 and behavioral responses as well as the expression profile in hippocampus of prokineticin 2 and its receptors were investigated. Results demonstrated that Aβ1–42-infused rats developed significant memory impairments together with a marked up-regulation of both prokineticin 2 and its receptors in hippocampal neurons and astrocytes. Treatment with PC1 significantly improved learning capability of Aβ1–42-infused rats restoring the balance of prokineticin system. This study pointed to a neuroprotective role of PC1 on Aβ1-42-induced memory deficits that could be ascribed to the ability of PC1 to modulate rat hippocampal prokineticin system and to recover the impaired Aβ1-42-induced neurogenesis. This suggests that prokineticin system antagonism could be considered as a new approach for the study of AD etiopathology. •Intracerebroventricolar infusion of Aβ1-42 modulates prokineticin system in rats.•PC1 improves learning capability of Aβ1–42-infused rats decreasing PROK2 levels.•PC1 restores the impaired Aβ1-42-induced neurogenesis in hippocampus.•PC1 decreases iNOS and NF-κB overexpression reducing Aβ1-42-induced gliosis.