Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, China.
Guangzhou University of Chinese Medicine, Guangzhou, China.
Oxid Med Cell Longev. 2022 Aug 8;2022:5392966. doi: 10.1155/2022/5392966. eCollection 2022.
Chronic cerebral hypoperfusion (CCH) is a cardinal risk factor for Parkinson's disease dementia (PDD), but this potential causality lacks mechanistic evidence. We selected bilateral common carotid artery occlusion (BCCAO) to simulate chronic cerebral hypoperfusion in the rat model of PD induced by typical neurotoxin 6-hydroxy dopamine (6-OHDA). Four weeks after unilateral injection of 6-OHDA into the medial forebrain bundle, rats underwent BCCAO. Male Sprague-Dawley rats were divided into five groups of ten, including sham, PD+BCCAO 2 weeks, PD+BCCAO 1 week, PD, and BCCAO 2 weeks. Then, open field test (OFT) and water maze test (MWM) were used to assess the PDD-like symptoms in rats. Also, the pathological manifestations and mechanisms of BCCAO impairing cognitive functions have been explored via hematoxylin-eosin staining, Nissl staining, immunohistochemistry, immunofluorescence, RNA sequencing analysis, lipidomics, and quantitative real-time polymerase chain reaction. In this study, we found that CCH could aggravate PDD-like cognitive symptoms (i.e., learning memory and spatial cognition) and PDD-like pathology (higher expression of -Syn and A in prefrontal cortex and striatum). Moreover, a potential relationship between differentially expressed mRNAs and lipid metabolism was revealed by RNA sequencing analysis. Lipidomics showed that CCH could affect the intensity of 5 lipids, including sphingomyelin (SM 9:0;2O/26:2; SM 8:1;2O/25:0; and SM 8:0;2O/28:4), cardiolipin, lysophosphatidylcholine, cholesteryl ester, and triacylglycerol. Interestingly, the KEGG pathway analysis of both RNA sequencing analysis and lipidomics suggested that CCH leaded to learning impairment by affecting sphingolipid metabolism. Finally, we found that CCH disrupts the sphingolipid metabolism by affecting the mRNA expression of SMPD1 and SMS2, leading to the accumulation of sphingomyelin in the prefrontal cortex. In summary, CCH, an independent exacerbating reason for impairment in learning and memory within the pathopoiesis of PD, aggravates Parkinson's disease dementia-like symptoms and pathology in 6-OHDA-lesioned rat through interfering with sphingolipid metabolism.
慢性脑灌注不足 (CCH) 是帕金森病痴呆症 (PDD) 的主要危险因素，但这种潜在的因果关系缺乏机制证据。我们选择双侧颈总动脉闭塞 (BCCAO) 来模拟由典型神经毒素 6-羟基多巴胺 (6-OHDA) 诱导的 PD 大鼠模型中的慢性脑灌注不足。在中脑束内侧单侧注射 6-OHDA 4 周后，大鼠行 BCCAO。雄性 Sprague-Dawley 大鼠分为五组，每组 10 只，包括假手术组、PD+BCCAO2 周组、PD+BCCAO1 周组、PD 组和 BCCAO2 周组。然后，通过旷场试验 (OFT) 和水迷宫试验 (MWM) 评估大鼠的 PDD 样症状。此外，还通过苏木精-伊红染色、尼氏染色、免疫组织化学、免疫荧光、RNA 测序分析、脂质组学和实时定量聚合酶链反应探索了 BCCAO 损害认知功能的病理表现和机制。在这项研究中，我们发现 CCH 可加重 PDD 样认知症状（即学习记忆和空间认知）和 PDD 样病理（前额叶皮层和纹状体中 -Syn 和 A 的表达升高）。此外，RNA 测序分析显示，差异表达的 mRNAs 与脂质代谢之间存在潜在关系。脂质组学表明，CCH 可影响 5 种脂质的强度，包括神经鞘磷脂 (SM 9:0;2O/26:2; SM 8:1;2O/25:0; 和 SM 8:0;2O/28:4)、心磷脂、溶血磷脂酰胆碱、胆固醇酯和三酰甘油。有趣的是，RNA 测序分析和脂质组学的 KEGG 通路分析表明，CCH 通过影响鞘脂代谢导致学习障碍。最后，我们发现 CCH 通过影响 SMPD1 和 SMS2 的 mRNA 表达干扰鞘脂代谢，导致前额叶皮层神经鞘磷脂堆积，从而破坏鞘脂代谢。综上所述，CCH 是 PD 发病机制中损害学习和记忆的独立加重因素，通过干扰鞘脂代谢加重 6-OHDA 损伤大鼠的帕金森病痴呆样症状和病理。
