CB1 Agonist ACEA Protects Neurons and Reduces the Cognitive Impairment of AβPP/PS1 Mice
CB1 Agonist ACEA Protects Neurons and Reduces the Cognitive Impairment of AβPP/PS1 Mice
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DOI：
10.3233/jad-2012-111862
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发表时间：
2012-01-01
影响因子：
4
通讯作者：
Ferrer, Isidro
中科院分区：
文献类型：
--
作者：
Aso, Ester;Palomer, Ernest;Ferrer, Isidro
本研究表明，在症状前或症状早期，以非失忆剂量慢性给药大麻素受体1型（CB1）受体激动剂花生四烯酰基-2-氯乙胺（ACEA），可减少6个月大的双a β PP(swe)/PS1（1dE9）转基因小鼠的认知功能障碍。ACEA对β淀粉样蛋白（A β）的产生、聚集或清除没有影响。然而，ACEA降低了皮质神经元原代培养中A β(42)寡聚物的细胞毒性作用，并在体外和体内逆转了A β诱导的糖原合成酶激酶3 β (GSK3 β)的去磷酸化。在A- β斑块周围的神经过程中磷酸化tau （Thr181）的减少进一步支持了乙酰胆酸处理小鼠中GSK3 β活性的降低。此外，与年龄匹配的转基因小鼠相比，乙酸处理小鼠在A β斑块附近的星形胶质细胞反应减少，星形胶质细胞中促炎细胞因子干扰素γ的表达减少。我们目前的结果显示，ACEA在神经元和胶质水平上都有有益的作用，至少部分是由GSK3 β抑制介导的，导致反应性星形胶质细胞减少，干扰素γ的表达降低。因此，靶向CB1受体可以为治疗阿尔茨海默病提供一种通用的方法。
The present study shows that chronic administration of the Cannabinoid receptor type 1 (CB1) receptor agonist arachidonyl-2-chloroethylamide (ACEA) at pre-symptomatic or at early symptomatic stages, at a non-amnesic dose, reduces the cognitive impairment observed in double A beta PP(swe)/PS1(1dE9) transgenic mice from 6 months of age onwards. ACEA has no effect on amyloid-beta (A beta) production, aggregation, or clearance. However, ACEA reduces the cytotoxic effect of A beta(42) oligomers in primary cultures of cortical neurons, and reverses A beta-induced dephosphorylation of glycogen synthase kinase-3 beta (GSK3 beta) in vitro and in vivo. Reduced activity of GSK3 beta in ACEA-treated mice is further supported by the reduced amount of phospho-tau (Thr181) in neuritic processes around A beta plaques. In addition, ACEA-treated mice show decreased astroglial response in the vicinity of A beta plaques and decreased expression of the pro-inflammatory cytokine interferon-gamma in astrocytes when compared with age-matched vehicle-treated transgenic mice. Our present results show a beneficial effect of ACEA at both the neuronal, mediated at least in part by GSK3 beta inhibition, and glial levels, resulting in a reduction of reactive astrocytes and lower expression of interferon-gamma. As a consequence, targeting the CB1 receptor could offer a versatile approach for the treatment of Alzheimer's disease.