CB2 Receptor Deficiency Increases Amyloid Pathology and Alters Tau Processing in a Transgenic Mouse Model of Alzheimer’s Disease

Abstract

The endocannabinoid CB 2 receptor system has been implicated in the neuropathology of Alzheimer's disease (AD). In order to investigate the impact of the CB 2 receptor system on AD pathology, a colony of mice with a deleted CB 2 receptor gene, CNR2, was established on a transgenic human mutant APP background for pathological comparison with CB 2 receptor-sufficient transgenic mice. J20 APP (PDGFB-APPSwInd) mice were bred over two generations with CNR2 -/-(Cnr2 tm1Dgen /J) mice to produce a colony of J20 CNR2 +/+ and J20 CNR2 -/-mice. Seventeen J20 CNR2 +/+ mice (12 females, 5 males) and 16 J20 CNR2 -/-mice (11 females, 5 males) were killed at 12 months, and their brains were interrogated for AD-related pathology with both biochemistry and immunocytochemistry (ICC). In addition to amyloid-dependent endpoints such as soluble Aβ production and plaque deposition quantified with 6E10 staining, the effect of CB 2 receptor deletion on total soluble mouse tau production was assayed by using a recently developed high-sensitivity assay. Results revealed that soluble Aβ42 and plaque deposition were significantly increased in J20 CNR2 -/-mice relative to CNR2 +/+ mice. Microgliosis, quantified with ionized calcium-binding adapter molecule 1 (Iba-1) staining, did not differ between groups, whereas plaque associated microglia was more abundant in J20 CNR2 -/-mice. Total tau was significantly suppressed in J20 CNR2 -/-mice relative to J20 CNR2 +/+ mice. The results confirm the constitutive role of the CB 2 receptor system both in reducing amyloid plaque pathology in AD and also support tehpotential of cannabinoid therapies targeting CB 2 to reduce Aβ; however, the results suggest that interventions may have a divergent effect on tau pathology.

Cannabinoid receptor 2 deficiency results in reduced neuroinflammation in an Alzheimer's disease mouse model

“…The degree of Iba-1 staining observed in the brains of APP/PS1*CB2 À/À mice suggested reduced microgliosis in the absence of CB2. This is in contrast to data presented by Koppel et al (Koppel et al, 2013) that demonstrated enhanced levels of Iba1 staining in CB2 À/À mice using a different (J20 APP) genetic model of AD. Unfortunately, this study did not establish baseline Iba1 levels in CB2 À/À and CB2 þ/þ mice, data that would be of importance based on our observations that at baseline CB2 À/À mice presented increased levels of Iba1 staining.…”

CB2 Receptor in Microglia: The Guardian of Self-Control

“…Moreover, studies performed with late-symptomatic mice after CB2R deletion show contradicting results. Koppel et al reported an enhanced number of plaque-associated microglia in late-symptomatic mice after CB2R deletion accompanied by enhanced levels of soluble Aβ 42 levels and Aβ plaques [72]. In contrast, our study on latesymptomatic mice showed decreased levels of Aβ plaques.…”

“…In line with this finding, treating rats suffering from vascular dementia with HPβCD/BCP, a CB2R agonist, upregulated CB2R expression in the hippocampus and improved long-term spatial memory [130]. Moreover, as mentioned above, many different reports investigated the CB2 receptor in the context of AD and showed that the modulation of this receptor can influence learning and memory [51,72,73,131].…”

Cannabinoid CB2 Receptors in a Mouse Model of Aβ Amyloidosis: Immunohistochemical Analysis and Suitability as a PET Biomarker of Neuroinflammation

“…Recent in vivo studies in animal models of AD demonstrated an ameliorating effect of CB2 receptor agonists on cognitive deficits in these mice that was associated with decreased microglial reactivity, reduced expression of pro-inflammatory cytokines [ 78 , 79 ] and some decreases in Aβ accumulation after longer periods of treatments [ 79 ]. Genetic ablation of CB2 receptors in amyloid-producing mice resulted in opposing but significant effects on Aβ plaque load in different models [ 80 , 81 ] indicating that effects of CB2 receptors is likely to depend of the stage of amyloidosis and other factors.…”