Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB, UNS-CONICET), Edificio E1, Camino La Carrindanga Km 7, 8000 Bahía Blanca, Argentina; Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, San Juan 670, 8000 Bahía Blanca, Argentina.
Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB, UNS-CONICET), Edificio E1, Camino La Carrindanga Km 7, 8000 Bahía Blanca, Argentina; Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, San Juan 670, 8000 Bahía Blanca, Argentina.
Neuroscience. 2017 Oct 24;362:168-180. doi: 10.1016/j.neuroscience.2017.08.042. Epub 2017 Aug 24.
Alzheimer's disease (AD) is the most prevalent disorder of senile dementia mainly characterized by amyloid-beta peptide (Aβ) deposits in the brain. Cannabinoids are relevant to AD as they exert several beneficial effects in many models of this disease. Still, whether the endocannabinoid system is either up- or down-regulated in AD has not yet been fully elucidated. Thus, the aim of the present paper was to analyze endocannabinoid 2-arachidonoylglycerol (2-AG) metabolism in cerebral cortex synaptosomes incubated with Aβ oligomers or fibrils. These Aβ conformations were obtained by "aging" the 1-40 fragment of the peptide under different agitation and time conditions. A diminished availability of 2-AG resulting from a significant decrease in diacylglycerol lipase (DAGL) activity was observed in the presence of large Aβ oligomers along with synaptosomal membrane damage, as judged by transmission electron microscopy and LDH release. Conversely, a high availability of 2-AG resulting from an increase in DAGL and lysophosphatidic acid phosphohydrolase activities occurred in the presence of Aβ fibrils although synaptosomal membrane disruption was also observed. Interestingly, neither synaptosomal mitochondrial viability assayed by MTT reduction nor membrane lipid peroxidation assayed by TBARS formation measurements were altered by Aβ oligomers or fibrils. These results show a differential effect of Aβ peptide on 2-AG metabolism depending on its conformation.
阿尔茨海默病（AD）是最常见的老年痴呆症，主要特征是大脑中淀粉样β肽（Aβ）沉积。大麻素与 AD 相关，因为它们在许多这种疾病的模型中发挥了多种有益作用。然而，AD 中内源性大麻素系统是上调还是下调尚未完全阐明。因此，本研究的目的是分析在 Aβ 寡聚体或纤维存在下培养的大脑皮质突触体中的内源性大麻素 2-花生四烯酰甘油（2-AG）代谢。通过在不同搅拌和时间条件下对肽的 1-40 片段进行“老化”，获得了这些 Aβ 构象。在存在大 Aβ 寡聚体的情况下，观察到 2-AG 的可用性降低，这是由于二酰基甘油脂肪酶（DAGL）活性显著下降所致，这可以通过透射电子显微镜和 LDH 释放来判断。相反，在存在 Aβ 纤维的情况下，2-AG 的可用性增加，这是由于 DAGL 和溶血磷脂酸磷酸水解酶活性增加所致，尽管也观察到突触体膜破裂。有趣的是，Aβ 寡聚体或纤维既没有改变突触体线粒体活力（通过 MTT 减少测定），也没有改变膜脂质过氧化（通过 TBARS 形成测量测定）。这些结果表明，Aβ 肽对 2-AG 代谢的影响取决于其构象。
