Delta8THC protects against amyloid beta toxicity modulating ER stress in vitro: a transcriptomic analysis

Alzheimer s disease (AD) represents the most common form of dementia, characterized by amyloid beta (Abeta) plaques and neurofibrillary tangles (NFTs). It is characterized by neuroinflammation, accumulation of misfolded protein, ER stress and apoptosis. It is of main importance to find new therapeutic strategies because its prevalence is increasing worldwide. Cannabinoids are promising neuroprotective phytocompounds and in particular non psychotropic ones are reaching attention. In this study we evaluated the neuroprotective potential of Delta8-THC pretreatment in an in vitro model of AD through transcriptomic analysis. We found that Delta8-THC pretreatment restored the loss of cell viability in retinoic acid-differentiated neuroblastoma SH-SY5Y cells treated with Abeta1-42. Moreover, transcriptomic analysis evidenced that enriched GO were related to ER functions and proteostasis. In particular, Abeta1-42 upregulated genes involved in ER stress and unfolded protein response, leading to apoptosis as demonstrated by the increase of Bax and decrease of Bcl-2 both at gene and protein expression levels. On the contrary, Delta8-THC pre-treatment reduced ER stress and as a consequence apoptosis. Then, the results demonstrated that Delta8-THC may represent a new neuroprotective agent in AD.

阿尔茨海默病（Alzheimer's disease, AD）是最常见的痴呆类型，以β淀粉样蛋白（amyloid beta, Aβ）斑块和神经原纤维缠结（neurofibrillary tangles, NFTs）为核心病理特征，同时伴随神经炎症、错误折叠蛋白聚集、内质网应激（endoplasmic reticulum stress, ER stress）与细胞凋亡。鉴于其全球患病率持续攀升，研发新型治疗策略至关重要。大麻素类化合物是极具前景的神经保护植物源性成分，其中非精神活性大麻素愈发受到学界关注。本研究通过转录组学分析，评估了Δ8-四氢大麻酚（Delta8-THC）预处理在阿尔茨海默病体外模型中的神经保护潜力。研究发现，经Aβ1-42处理的视黄酸诱导分化神经母细胞瘤SH-SY5Y细胞中，Δ8-THC预处理可恢复其丧失的细胞活力。此外，转录组学分析结果显示，富集的基因本体（Gene Ontology, GO）条目与内质网功能及蛋白质稳态密切相关。具体而言，Aβ1-42可上调内质网应激与未折叠蛋白反应相关基因的表达，最终诱导细胞凋亡；这一效应可通过基因与蛋白水平上Bax表达上调、Bcl-2表达下调得到证实。与之相反，Δ8-THC预处理可减轻内质网应激，进而抑制细胞凋亡。综上，本研究结果表明Δ8-THC有望成为阿尔茨海默病的新型神经保护剂。