The role of the endocannabinoid receptor CB2 in a mouse model of Alzheimer's disease

Abstract

Over the past years, an important role of the cannabinoid receptor 2 (CB2) has been implicated in several neurological and immunological conditions, such as experimental autoimmune encephalitis, stroke, memory, neuropathic pain or Alzheimer's disease (AD).<br /> In AD transgenic mouse models, AD-associated neuroin ammatory processes were shown to decrease by the pharmacological stimulation with agonists of the endocannabinoid system (ECS), while age- and AD-associated cognitive deficits were diminished. However, the exact mechanism by which CB2 might be involved in these processes still remains elusive.<br /> Therefore, the current study was designed to analyse the effects of CB2 signalling on the one hand in microglia polarisation using<em> in vitro</em> cell-culture models. On the other hand, neuroin ammatory and neurodegenerative processes as well as changes in cognitive performances were evaluated in the AD transgenic mouse model APPswe/PS1dE9 (APP/PS1) and in mice lacking functional CB2 receptor expression (CB2^-/-).<br /> We demonstrate here that neonatal microglia derived from CB2^-/- mice were less responsive to pro-in ammatory stimuli when compared to microglia derived from wildtype mice. These findings were based on the cell surface marker expression of the intercellular adhesion molecule 1 (ICAM) and cluster of differentiation (CD) 40 as well as the release of the cytokines interleukin (IL) -6 and tumor necrosis factor (TNF) -α and the chemokine CCL2. Furthermore, we found a reduced amyloid-β (Aβ) plaque load in hippocampal and cortical regions, a reduced microgliosis, diminished markers of neuroin ammation as well as a decreased neurodegeneration in aged APP/PS1*CB2^-/- mice when compared to samples of age-matched APP/PS1 mice. Finally, we could demonstrate that spatial learning and memory deficits were rescued in aged APP/PS1*CB2^-/- mice.<br /> These data suggest that microglia polarisation is alternatively altered in the absence of CB2 signalling and positively in uenced AD-associated neuroin ammation in the present mouse model.