CB receptor deficiency increases amyloid pathology and alters tau processing in a transgenic mouse model of Alzheimer's disease.
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The endocannabinoid CB receptor system has been implicated in the neuropathology of Alzheimer's disease (AD). In order to investigate the impact of the CB receptor system on AD pathology, a colony of mice with a deleted CB receptor gene, CNR2, was established on a transgenic human mutant APP background for pathological comparison with CB 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 A production and plaque deposition quantified with 6E10 staining, the effect of CB2 receptor deletion on total soluble mouse tau production was assayed by using a recently developed high-sensitivity assay. Results revealed that soluble A42 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 receptor system both in reducing amyloid plaque pathology in AD and also support tehpotential of cannabinoid therapies targeting CB to reduce A; however, the results suggest that interventions may have a divergent effect on tau pathology.
author list (cited authors)
Koppel, J., Vingtdeux, V., Marambaud, P., d'Abramo, C., Jimenez, H., Stauber, M., Friedman, R., & Davies, P.