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.

Association of CD33 polymorphism rs3865444 with Alzheimer's disease pathology and CD33 expression in human cerebral cortex

“…This might suggest that there are greater numbers of microglia in A/A cases, though this would not agree with a previous finding (Bradshaw et al, 2013); alternatively the microglia in the A/A cases might be more activated as a result of reduced CD33 anti-inflammatory activity. IBA-1 (ionized calcium binding adapter protein-1) is a widely used marker to assess microglial abundance, though its expression can also be upregulated with microglial activation (Koppel et al, 2014;Puli et al, 2012;Zotova et al, 2013). Reduced amounts of CD33 protein was a feature of peripheral blood monocytes from A/A subjects (Bradshaw et al, 2013).…”

Endocannabinoid system in neurodegenerative disorders

“…APP/PS1 mice lacking CB2R exhibit increased Aβ deposits in cerebral cortex, hippocampus, and cortical Aβ40 soluble levels in the early symptomatic phase (6 months) but not in the pre‐symptomatic phase (3 months) (Koppel et al . ; Aso et al . ).…”

Toward more predictive genetic mouse models of Alzheimer's disease

“…Amyloid reduction therapies have been shown to lead to the undesired increase in tau phosphorylation as a consequence, and the inverse is also true: antagonism of tau phosphorylation also results in an increase in amyloidosis [39, 41]. Earlier this year Calafate and colleagues (2015) demonstrated in vitro neuron-to-neuron transmission of tau across the synapse[42].…”

“…This phenotype is present in AD mouse models. CRN2 KO mice show an increase in amyloidosis and alterations in tau processing that led to a decrease in measures of total tau [41]. Taken together, this suggests that CB2 should be considered as a marker of neuroinflammation.…”