Abstract
The endocannabinoid CB₂ receptor system has been implicated in the neuropathology of Alzheimer's disease (AD). In order to investigate the impact of the CB₂ receptor system on AD pathology, a colony of mice with a deleted CB₂ receptor gene, CNR2, was established on a transgenic human mutant APP background for pathological comparison with CB₂ 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 CB2 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 CB₂ receptor system both in reducing amyloid plaque pathology in AD and also support tehpotential of cannabinoid therapies targeting CB₂ to reduce Aβ; however, the results suggest that interventions may have a divergent effect on tau pathology.
Highlights
The primary neuropathological hallmarks of Alzheimer’s disease (AD) comprise amyloid-β (Aβ) deposits and neurofibrillary tangles composed of abnormally phosphorylated tau protein in the brain parenchyma [1]
Because there have been reports of amyloid production being influenced by gender in transgenic models [34], the groups were matched for gender
When AD brains are compared with controls, both levels of soluble and insoluble Aβ increase, but there is a shift from soluble forms to insoluble forms such that, in AD, insoluble Aβ dominates the total fraction of amyloid in the brain, whereas in healthy controls, soluble forms predominate [36]
Summary
The primary neuropathological hallmarks of Alzheimer’s disease (AD) comprise amyloid-β (Aβ) deposits and neurofibrillary tangles composed of abnormally phosphorylated tau protein in the brain parenchyma [1]. Deposition of Aβ in brain is known to induce microgliosis [2] and attendant cytokine production [3], events believed to be important drivers of the pathogenic cascade [4]. The endocannabinoid system comprises at least two biolipid signaling molecules produced on demand in a wide spectrum of cell types and tissues, in-. Cluding neurons and immune cells of the central nervous system, that bind to at least two cannabinoid receptors, CB1 and CB2 [5]. The CB2 receptor is expressed primarily in immune-competent cells and functions as a feedback inhibitor of inflammatory cytokine production [6]. This study was followed by an investigation of mRNA expression in the blood of subjects with AD in which expression of CB2 RECEPTOR DEFICIENCY IN AN AMYLOID MOUSE MODEL
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