Aso Ester, Andrés-Benito Pol, Carmona Margarita, Maldonado Rafael, Ferrer Isidre
Institut de Neuropatologia, Servei d'Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Spain.
CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto Carlos III, Spain.
J Alzheimers Dis. 2016;51(2):489-500. doi: 10.3233/JAD-150913.
The endogenous cannabinoid system represents a promising therapeutic target to modify neurodegenerative pathways linked to Alzheimer's disease (AD). The aim of the present study was to evaluate the specific contribution of CB2 receptor to the progression of AD-like pathology and its role in the positive effect of a cannabis-based medicine (1:1 combination of Δ9-tetrahidrocannabinol and cannabidiol) previously demonstrated to be beneficial in the AβPP/PS1 transgenic model of the disease. A new mouse strain was generated by crossing AβPP/PS1 transgenic mice with CB2 knockout mice. Results show that lack of CB2 exacerbates cortical Aβ deposition and increases the levels of soluble Aβ40. However, CB2 receptor deficiency does not affect the viability of AβPP/PS1 mice, does not accelerate their memory impairment, does not modify tau hyperphosphorylation in dystrophic neurites associated to Aβ plaques, and does not attenuate the positive cognitive effect induced by the cannabis-based medicine in these animals. These findings suggest a minor role for the CB2 receptor in the therapeutic effect of the cannabis-based medicine in AβPP/PS1 mice, but also constitute evidence of a link between CB2 receptor and Aβ processing.
内源性大麻素系统是一个很有前景的治疗靶点，可用于改变与阿尔茨海默病（AD）相关的神经退行性通路。本研究的目的是评估CB2受体对AD样病理进展的具体作用，以及它在一种大麻类药物（Δ9-四氢大麻酚和大麻二酚1:1组合）的积极作用中的角色，该药物先前已被证明对该疾病的AβPP/PS1转基因模型有益。通过将AβPP/PS1转基因小鼠与CB2基因敲除小鼠杂交，培育出了一种新的小鼠品系。结果显示，缺乏CB2会加剧皮质Aβ沉积，并增加可溶性Aβ40的水平。然而，CB2受体缺陷并不影响AβPP/PS1小鼠的生存能力，不会加速其记忆障碍，不会改变与Aβ斑块相关的营养不良性神经突中的tau过度磷酸化，也不会减弱这种大麻类药物在这些动物中诱导的积极认知效果。这些发现表明，CB2受体在大麻类药物对AβPP/PS1小鼠的治疗效果中作用较小，但也构成了CB2受体与Aβ加工之间存在联系的证据。
