Aims: This study is to investigate the effects of Cannabinoid type 2 receptor (CB2R) deficiency on microglia and cognitive function in both A beta(1-42)-injected CB2R knockout mice and a transgenic mouse model of Alzheimer's disease (AD) in brain. Methods: After hippocampal injection with A beta(1-42) oligomers in CB2R knockout mice with and without CB2R agonist treatment and in transgenic APP/PS1 mice with CB2R deletion, the novel object recognition (NOR) and Morris water maze (MWM) tests were performed to assess the animal behavior performance. Immunofluorescence staining was conducted to detect the microglial morphology and activation status. The expression of proinflammation and anti-inflammation cytokines were determined by qRT-PCR. Results: CB2R deficiency significantly aggravated cognitive impairment in both A beta(1-42)-induced and transgenic APP/PS1 animal model in NOR. In A beta-injected mice lacking CB2R and transgenic APP/PS1 mice with CB2R deletion, microglia in the prefrontal cortex exhibited enhanced immunoreactivity with altered morphology. Furthermore, transformation of activated microglial phenotype in the prefrontal cortex was reduced in A beta(1-42)-injected CB2R knockout mice after CB2R agonist treatment. The CB2R deficiency significantly increased the expression of proinflammatory cytokines in the prefrontal cortex, while it was observed in the hippocampus in both A beta(1-42)-injected and transgenic APP/PS1 AD mouse model. Furthermore, CB2R deficiency increased concentrations of soluble A beta (40) in the prefrontal cortex, but did not affect plaques deposition. Conclusion: CB2R deletion led to enhanced neuroinflammatory responses via direct upregulating microglia activation in the prefrontal cortex during the early symptomatic phase of AD mice. CB2R modulates prefrontal cortical neuroinflammation, which is essential for regulating cognitive functions such as recognition memory at the early stage of AD.