{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T05:42:44Z","timestamp":1775454164129,"version":"3.50.1"},"reference-count":45,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,8,8]],"date-time":"2022-08-08T00:00:00Z","timestamp":1659916800000},"content-version":"vor","delay-in-days":219,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2022A151510450"],"award-info":[{"award-number":["2022A151510450"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012151","name":"Sanming Project of Medicine in Shenzen Municipality","doi-asserted-by":"publisher","award":["SZZYSM202106009"],"award-info":[{"award-number":["SZZYSM202106009"]}],"id":[{"id":"10.13039\/501100012151","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Oxidative Medicine and Cellular Longevity"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:p>Chronic cerebral hypoperfusion (CCH) is a cardinal risk factor for Parkinson\u2019s 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\u2010hydroxy dopamine (6\u2010OHDA). Four weeks after unilateral injection of 6\u2010OHDA into the medial forebrain bundle, rats underwent BCCAO. Male Sprague\u2010Dawley 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 <jats:italic>Morris<\/jats:italic> water maze test (MWM) were used to assess the PDD\u2010like symptoms in rats. Also, the pathological manifestations and mechanisms of BCCAO impairing cognitive functions have been explored via hematoxylin\u2010eosin staining, Nissl staining, immunohistochemistry, immunofluorescence, RNA sequencing analysis, lipidomics, and quantitative real\u2010time polymerase chain reaction. In this study, we found that CCH could aggravate PDD\u2010like cognitive symptoms (i.e., learning memory and spatial cognition) and PDD\u2010like pathology (higher expression of <jats:italic>\u03b1<\/jats:italic>\u2010Syn and A<jats:italic>\u03b2<\/jats:italic> 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\u2019s disease dementia\u2010like symptoms and pathology in 6\u2010OHDA\u2010lesioned rat through interfering with sphingolipid metabolism.<\/jats:p>","DOI":"10.1155\/2022\/5392966","type":"journal-article","created":{"date-parts":[[2022,8,8]],"date-time":"2022-08-08T21:05:09Z","timestamp":1659992709000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Chronic Cerebral Hypoperfusion Aggravates Parkinson\u2019s Disease Dementia\u2010Like Symptoms and Pathology in 6\u2010OHDA\u2010Lesioned Rat through Interfering with Sphingolipid 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