Gray Sarah M, Dai Jing, Smith Anne C, Beckley Jacob T, Rahmati Negah, Lewis Michael C, Quirk Michael C
Sage Therapeutics Inc, Cambridge, MA, USA.
J Huntingtons Dis. 2024 Nov;13(4):449-465. doi: 10.3233/JHD-240030.
There is evidence for dysregulated cholesterol homeostasis in Huntington's disease (HD). The brain-specific cholesterol metabolite 24(S)-hydroxycholesterol (24(S)-OHC) is decreased in manifest HD. 24(S)-OHC is an endogenous positive allosteric modulator (PAM) of the N-methyl-D-aspartate (NMDA) receptor, suggesting lower 24(S)-OHC may contribute to NMDA receptor hypofunction in HD. We hypothesized changes in 24(S)-OHC would be associated with cognitive impairment in early HD.
To determine the interactions between oxysterols (24(S)-OHC, 25-OHC, and 27-OHC) at the NMDA receptor, the plasma levels of these oxysterols, and how these levels relate to cognitive performance.
An competition assay was used to evaluate interactions at the NMDA receptor, liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) was used to measure plasma 24(S)-OHC, 25-OHC, and 27-OHC levels, and correlation analyses investigated their relationship to performance on cognitive endpoints in TRACK and ENROLL-HD (NCT01574053).
, 25-OHC and 27-OHC attenuated the PAM activity of 24(S)-OHC on the NMDA receptor. Lower plasma 24(S)-OHC levels and 24(S)/25-OHC ratios were detected in participants with early HD. Moderate and consistent associations were detected between plasma 24(S)/25-OHC ratio and performance on Stroop color naming, symbol digit modality, Trails A/B, and emotion recognition. Little association was observed between the ratio and psychiatric or motor endpoints, suggesting specificity for the relationship to cognitive performance.
Our findings support growing evidence for dysregulated CNS cholesterol homeostasis in HD, demonstrate a relationship between changes in oxysterols and cognitive performance in HD, and propose that NMDA receptor hypofunction may contribute to cognitive impairment in HD.
有证据表明亨廷顿舞蹈症（HD）患者存在胆固醇稳态失调。在显性HD患者中，脑特异性胆固醇代谢产物24(S)-羟基胆固醇（24(S)-OHC）水平降低。24(S)-OHC是N-甲基-D-天冬氨酸（NMDA）受体的内源性正变构调节剂（PAM），这表明较低的24(S)-OHC水平可能导致HD患者的NMDA受体功能减退。我们推测24(S)-OHC的变化可能与早期HD患者的认知障碍有关。
确定氧化甾醇（24(S)-OHC、25-OHC和27-OHC）在NMDA受体上的相互作用、这些氧化甾醇的血浆水平，以及这些水平与认知表现的关系。
采用竞争试验评估在NMDA受体上的相互作用，使用液相色谱串联质谱法（LC-MS/MS）测量血浆中24(S)-OHC、25-OHC和27-OHC水平，并通过相关分析研究它们与TRACK和ENROLL-HD（NCT01574053）研究中认知终点表现的关系。
25-OHC和27-OHC减弱了24(S)-OHC对NMDA受体的PAM活性。在早期HD患者中检测到较低的血浆24(S)-OHC水平和24(S)/25-OHC比值。血浆24(S)/25-OHC比值与Stroop颜色命名、符号数字模式、连线测验A/B和情绪识别表现之间存在中度且一致的相关性。该比值与精神或运动终点之间几乎没有关联，表明其与认知表现的关系具有特异性。
我们的研究结果支持越来越多的证据表明HD患者中枢神经系统胆固醇稳态失调，证明了氧化甾醇变化与HD患者认知表现之间的关系，并提出NMDA受体功能减退可能导致HD患者的认知障碍。
