Cannabinoid type 2 receptor deficiency leads to Aβ-induced cognitive impairment through promoting microglial sensitivity to Aβ in the prefrontal cortex in mice

Aims

This study is to investigate the effects of Cannabinoid type 2 receptor (CB₂R) deficiency on microglia and cognitive function in both Aβ_1–42-injected CB₂R knockout mice and a transgenic mouse model of Alzheimer’s disease (AD) in brain.

Methods

After hippocampal injection with Aβ_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 Aβ_1–42-induced and transgenic APP/PS1 animal model in NOR. In Aβ-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 Aβ_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 Aβ_1–42-injected and transgenic APP/PS1 AD mouse model. Furthermore, CB₂R deficiency increased concentrations of soluble Aβ 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.