Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Via Vetoio Snc, 67100 L'Aquila, Italy.
European Center for Brain Research-IRCCS Santa Lucia Foundation (FSL), Via del Fosso di Fiorano 64, 00143 Rome, Italy.
Int J Mol Sci. 2023 Apr 3;24(7):6684. doi: 10.3390/ijms24076684.
Dysfunctional phenotype of microglia, the primary brain immune cells, may aggravate Alzheimer's disease (AD) pathogenesis by releasing proinflammatory factors, such as nitric oxide (NO). The endocannabinoids -arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) are bioactive lipids increasingly recognised for their essential roles in regulating microglial activity both under normal and AD-driven pathological conditions. To investigate the possible impact of chronic exposure to β-amyloid peptides (Aβ) on the microglial endocannabinoid signalling, we characterised the functional expression of the endocannabinoid system on neonatal microglia isolated from wild-type and Tg2576 mice, an AD-like model, which overexpresses Aβ peptides in the developing brain. We found that Aβ-exposed microglia produced 2-fold more 2-AG than normal microglia. Accordingly, the expression levels of diacylglycerol lipase-α (DAGLα) and monoacylglycerol lipase (MAGL), the main enzymes responsible for synthesising and hydrolysing 2-AG, respectively, were consistently modified in Tg2576 microglia. Furthermore, compared to wild-type cells, transgenic microglia basally showed increased expression of the cannabinoid 2 receptor, typically upregulated in an activated proinflammatory phenotype. Indeed, following inflammatory stimulus, Aβ-exposed microglia displayed an enhanced production of NO, which was abolished by pharmacological inhibition of DAGLα. These findings suggested that exposure to Aβ polarises microglial cells towards a pro-AD phenotype, possibly by enhancing 2-AG signalling.
小胶质细胞是大脑主要的免疫细胞，其功能障碍表型可能通过释放促炎因子（如一氧化氮 [NO]）而加重阿尔茨海默病（AD）的发病机制。内源性大麻素 - 花生四烯酸乙醇胺（AEA）和 2-花生四烯酸甘油（2-AG）是生物活性脂质，越来越多地被认为在调节小胶质细胞活性方面发挥着重要作用，无论是在正常状态还是 AD 驱动的病理状态下。为了研究慢性暴露于 β-淀粉样肽（Aβ）对小胶质细胞内源性大麻素信号转导的可能影响，我们对来自野生型和 Tg2576 小鼠（一种在发育中的大脑中过度表达 Aβ 肽的 AD 样模型）的新生小胶质细胞的内源性大麻素系统的功能表达进行了表征。我们发现，Aβ 暴露的小胶质细胞比正常小胶质细胞产生 2 倍的 2-AG。相应地，二酰基甘油脂肪酶-α（DAGLα）和单酰基甘油脂肪酶（MAGL）的表达水平分别是合成和水解 2-AG 的主要酶，在 Tg2576 小胶质细胞中也被一致修饰。此外，与野生型细胞相比，转基因小胶质细胞基础表达水平增加了大麻素 2 型受体，通常在激活的促炎表型中上调。事实上，与野生型细胞相比，在炎症刺激下，Aβ 暴露的小胶质细胞表现出增强的 NO 产生，而 DAGLα 的药理学抑制则消除了这种产生。这些发现表明，Aβ 暴露会使小胶质细胞向促 AD 表型极化，可能是通过增强 2-AG 信号转导。
