Work

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

Year: 2024

Type: article

Abstract: Aims This study is to investigate the effects of Cannabinoid type 2 receptor (CB 2 R) deficiency on microglia and cognitive function in both Aβ 1–42 -injected CB 2 R knockout mice and a transgenic mouse model of Alzheimer's disease (AD) in brain. Methods After hippocampal injection with Aβ 1–42 oligomers in CB 2 R knockout mice with and without CB 2 R agonist treatment and in transgenic APP/PS1 mice with CB 2 R 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 CB 2 R deficiency significantly aggravated cognitive impairment in both Aβ 1–42 -induced and transgenic APP/PS1 animal model in NOR. In Aβ-injected mice lacking CB 2 R and transgenic APP/PS1 mice with CB 2 R 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 CB 2 R knockout mice after CB 2 R agonist treatment. The CB 2 R 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, CB 2 R deficiency increased concentrations of soluble Aβ 40 in the prefrontal cortex, but did not affect plaques deposition. Conclusion CB 2 R deletion led to enhanced neuroinflammatory responses via direct upregulating microglia activation in the prefrontal cortex during the early symptomatic phase of AD mice. CB 2 R modulates prefrontal cortical neuroinflammation, which is essential for regulating cognitive functions such as recognition memory at the early stage of AD.

Source: IBRO Neuroscience Reports

DOI: 10.1016/j.ibneur.2024.08.004