Department of Neurology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China.
Department of Interventional Neurology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China.
CNS Neurosci Ther. 2024 Nov;30(11):e70131. doi: 10.1111/cns.70131.
The study attempted to determine the underlying role and regulation mechanism of 3β-hydroxysterol-Δ24 reductase (DHCR24) in the pathophysiology of cerebral small vessel disease-associated cognitive impairment (CSVD-CI). An RNA high-throughput sequencing and independent verification were conducted to identify potential circRNAs becoming the upstream regulator.
RNA sequencing was performed in whole-blood samples in cohort 1 (10 CSVD-CI and 8 CSVD with cognitively normal [CSVD-CN] patients). The DHCR24 and candidate circRNAs were verified in an independent cohort 2 (45 CSVD-CI participants and 37 CSVD-CN ones). The study also analyzed comprehensive cognitive assessments, plasma molecular index, and brain structure imaging.
The expression of DHCR24 and has_circ_0015335 in whole-blood samples of CSVD-CI patients was significantly reduced compared to CSVD-CN patients in RNA sequencing and independent verification. Furthermore, the levels of DHCR24 and has_circ_0015335 were significantly related to global cognitive impairment in CSVD-CI patients. Meanwhile, DHCR24 could regulate the correlation between has_circ_0015335 expression and alterations in brain cortex in surface area, thickness, and volume in CSVD-CI patients. Additionally, hsa_circ_0015335 interacted with DHCR24 for plasma 24(S)-hydroxycholesterol levels among CSVD-CI patients.
Interaction between DHCR24 and hsa_circ_0015335 cognitively impaired CSVD by affecting brain cholesterol metabolism and brain structural changes.
本研究旨在确定 3β-羟甾醇-Δ24 还原酶（DHCR24）在与脑小血管病相关认知障碍（CSVD-CI）病理生理学中的作用和调节机制。通过 RNA 高通量测序和独立验证，确定潜在的环状 RNA 作为上游调控因子。
在队列 1（10 例 CSVD-CI 和 8 例认知正常的 CSVD [CSVD-CN]患者）的全血样本中进行 RNA 测序。在独立队列 2（45 例 CSVD-CI 参与者和 37 例 CSVD-CN 参与者）中验证 DHCR24 和候选 circRNAs。本研究还分析了全面的认知评估、血浆分子指标和脑结构成像。
与 CSVD-CN 患者相比，CSVD-CI 患者全血样本中 DHCR24 和 has_circ_0015335 的表达在 RNA 测序和独立验证中均显著降低。此外，DHCR24 和 has_circ_0015335 的水平与 CSVD-CI 患者的整体认知障碍显著相关。同时，DHCR24 可以调节 has_circ_0015335 表达与 CSVD-CI 患者大脑皮质表面积、厚度和体积变化之间的相关性。此外，hsa_circ_0015335 与 DHCR24 相互作用，影响 CSVD-CI 患者血浆 24（S）-羟胆固醇水平。
DHCR24 和 hsa_circ_0015335 之间的相互作用通过影响脑胆固醇代谢和脑结构变化导致 CSVD 患者认知障碍。
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