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Abstract：
Alzheimer\'s disease (AD) is a dementing, neurodegenerative disorder characterized by increased accumulation of beta-amyloid peptides (Aβ), degeneration of hippocampal neurons and the gradual development of learning and memory deficits. Therapeutically, there are still no ideal medicines available and this represents an urgent need for the development of new strategies to treat AD. Emerging lines of evidence suggest that modulation of the cannabinoid system exhibits neuroprotective effects in various neurological diseases, including AD. However, a consensus is yet to emerge as to the impact of hippocampal cannabinoid receptor 2 (CB2R) in protection of hippocampal neurons against Aβ induced neuronal toxicity. Here, we report that chronic treatment of primary hippocampal neuronal cultures with 100 nM Aβ1-42 oligomers for 7 days results in neurotoxicity, which includes increases in lactate dehydrogenase (LDH) levels, suggesting an Aβ1-42 -induced neuron apoptosis. Further, chronic Aβ1-42 reduces the ratio of phosphorylated Akt (pAkt)/Akt, in turn decreases neuronal Bcl-2/Bax ratio, and leads to an increase of caspase-3, which likely underlines the signal pathway of chronic Aβ1-42-induced neuron apoptosis. Interestingly, pre-treatments of CB2R agonist (JWH133, 10 μM) with Aβ1-42 prevents Aβ1-42-induced the decrease of pAkt/Akt ratio, the decrease of Bcl-2/Bax ratio, and the increase of caspase-3, and protects hippocampal neurons against Aβ1-42-induced apoptosis. All neuroprotective effects of JWH133 are abolished by a selective CB2R antagonist, AM630. Taken together, the activation of hippocampal CB2Rs protects neurons against Aβ1-42 toxicity, and the CB2R-mediated enhancement of the pAkt signaling is likely involved in the protection of hippocampal neurons against Aβ1-42-induced neuronal toxicity.
摘要：
阿尔茨海默病（AD）是一种痴呆症，以β-淀粉样肽（Aβ）积累增加为特征的神经退行性疾病，海马神经元的退化和学习记忆缺陷的逐渐发展。治疗学上,目前仍然没有理想的药物可用,这意味着迫切需要开发新的治疗AD的策略.新兴的证据表明，大麻素系统的调节在各种神经系统疾病中表现出神经保护作用，包括AD。然而,关于海马大麻素受体2（CB2R）在保护海马神经元免受Aβ诱导的神经元毒性中的影响，尚未达成共识。这里,我们报道，用100nMAβ1-42寡聚体慢性治疗7天可导致神经毒性，其中包括乳酸脱氢酶（LDH）水平的增加，提示Aβ1-42诱导的神经元凋亡。Further,慢性Aβ1-42降低磷酸化Akt（pAkt）/Akt的比率，反过来降低神经元Bcl-2/Bax比率，并导致caspase-3的增加，这可能强调了慢性Aβ1-42诱导的神经元凋亡的信号通路。有趣的是,用Aβ1-42预处理CB2R激动剂（JWH133，10μM）可防止Aβ1-42诱导的pAkt/Akt比值降低，Bcl-2/Bax比值的降低，和caspase-3的增加，并保护海马神经元免受Aβ1-42诱导的凋亡。JWH133的所有神经保护作用被选择性CB2R拮抗剂消除，AM630.一起来看,海马CB2R的激活保护神经元免受Aβ1-42毒性，CB2R介导的pAkt信号增强可能参与保护海马神经元免受Aβ1-42诱导的神经元毒性。
