title: CB₂ receptor deficiency increases amyloid pathology and alters tau processing in a transgenic mouse model of Alzheimer's disease.
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.
authors.affiliation: Litwin-Zucker Research Center, Feinstein Institute for Medical Research, North-Shore Long Island Jewish Health System, Manhasset, New York, United States of America.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Koppel
authors.affiliation: Litwin-Zucker Research Center, Feinstein Institute for Medical Research, North-Shore Long Island Jewish Health System, Manhasset, New York, United States of America.
authors.forename: Valerie
authors.initials: V
authors.lastname: Vingtdeux
authors.affiliation: Litwin-Zucker Research Center, Feinstein Institute for Medical Research, North-Shore Long Island Jewish Health System, Manhasset, New York, United States of America.
authors.forename: Philippe
authors.initials: P
authors.lastname: Marambaud
authors.affiliation: Litwin-Zucker Research Center, Feinstein Institute for Medical Research, North-Shore Long Island Jewish Health System, Manhasset, New York, United States of America.
authors.forename: Cristina
authors.initials: C
authors.lastname: d'Abramo
authors.affiliation: Litwin-Zucker Research Center, Feinstein Institute for Medical Research, North-Shore Long Island Jewish Health System, Manhasset, New York, United States of America.
authors.forename: Heidy
authors.initials: H
authors.lastname: Jimenez
authors.affiliation: Yeshiva University, New York, New York, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Stauber
authors.affiliation: Queens College, New York, New York, United States of America.
authors.forename: Rachel
authors.initials: R
authors.lastname: Friedman
authors.affiliation: Litwin-Zucker Research Center, Feinstein Institute for Medical Research, North-Shore Long Island Jewish Health System, Manhasset, New York, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Davies
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology*; D058225:Plaque, Amyloid / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics* / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C558298:Mapt protein, mouse; D043885:Receptor, Cannabinoid, CB2; D016875:tau Proteins