Degeneration and energy shortage in the suprachiasmatic nucleus underlies the circadian rhythm disturbance in ApoE(-/-) mice: implications for Alzheimer's disease.
Degeneration and energy shortage in the suprachiasmatic nucleus underlies the circadian rhythm disturbance in ApoE(-/-) mice: implications for Alzheimer's disease.
复制标题
视交叉上核的变性和能量短缺是 ApoE(-/-) 小鼠昼夜节律紊乱的基础：对阿尔茨海默病的影响
DOI：
10.1038/srep36335
复制
发表时间：
2016-11-08
影响因子：
4.6
通讯作者：
Cao JM
中科院分区：
文献类型：
--
作者：
Zhou L;Gao Q;Nie M;Gu JL;Hao W;Wang L;Cao JM
阿尔茨海默病（AD）患者患有睡眠障碍和昼夜节律紊乱（CRD）。其潜在机制尚未完全了解，并且缺乏治疗方法。在这项研究中，我们在AD模型ApoE−/−小鼠中表征了运动活动，时钟基因表达，视交叉上核（SCN）的形态学变性和能量代谢，以及视网膜光感。与对照组C57 BL/6 J小鼠相比，ApoE−/−小鼠在昏暗的光线和恒定的黑暗下表现出紊乱的昼夜运动活动，对相变时间表的再夹带受损。在ApoE−/−小鼠中，视网膜黑视蛋白表达减少，以及淀粉样变性和tau蛋白沉积明显。在ApoE−/− SCN中也观察到线粒体和突触退化、SIRT 1介导的能量代谢和时钟基因表达改变。补充脂肪或酮体但不补充葡萄糖，或腹膜内给予烟酰胺，恢复了SIRT 1和时钟基因的运动节律和昼夜节律表达，并减少了神经退行性变。两者合计，ApoE缺乏诱导变性和SCN节律性的显着干扰。视网膜光感下降和SCN结构和代谢恶化代表了ApoE−/−小鼠CRD的主要病理。我们的治疗实验可能有助于开发未来的治疗方法来治疗AD患者的CRD和睡眠障碍。
Alzheimer’s disease (AD) patients suffer sleep disorders and circadian rhythm disturbances (CRDs). The underlying mechanisms are incompletely understood, and treatments are lacking. In this study, we characterized the locomotor activity, clock gene expression, morphological degeneration and energy metabolism of suprachiasmatic nucleus (SCN), together with retinal light sensing, in ApoE−/− mice, a model for AD. Compared with the control C57BL/6J mice, ApoE−/− mice exhibited disordered circadian locomotor activity under dim light and constant darkness, with impaired re-entrainment to phase change schedules. Decreased retinal melanopsin expression, together with amyloidosis and tau deposition, was evident in ApoE−/− mice. Mitochondrial and synaptic deterioration, altered SIRT1-mediated energy metabolism and clock gene expression were also observed in ApoE−/− SCN. Supplementation with fat or ketone bodies but not glucose, or intraperitoneal administration of nicotinamide, restored the locomotor rhythmicity and circadian expression of SIRT1 and clock genes, as well as reducing neurodegeneration. Taken together, ApoE deficiency induced degeneration and a significant disturbance in the SCN rhythmicity. Decline of retinal light sensing and SCN structural and metabolic deteriorations represented the major pathologies accounting for the CRDs in ApoE−/− mice. Our curative experiments may help develop future therapies to treat the CRDs and sleep disorders in AD patients.
登录
查看更多内容
影响因子：
16.2
作者：
Herskovits AZ;Guarente L
通讯作者：
Guarente L
DOI：
10.1126/science.1243417
发表时间：
2013-11-01
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Peek CB;Affinati AH;Ramsey KM;Kuo HY;Yu W;Sena LA;Ilkayeva O;Marcheva B;Kobayashi Y;Omura C;Levine DC;Bacsik DJ;Gius D;Newgard CB;Goetzman E;Chandel NS;Denu JM;Mrksich M;Bass J
通讯作者：
Bass J
DOI：
10.1016/j.jalz.2014.01.006
发表时间：
2015-01
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Newport MT;VanItallie TB;Kashiwaya Y;King MT;Veech RL
通讯作者：
Veech RL
DOI：
10.1126/science.1171641
发表时间：
2009-05-01
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Ramsey KM;Yoshino J;Brace CS;Abrassart D;Kobayashi Y;Marcheva B;Hong HK;Chong JL;Buhr ED;Lee C;Takahashi JS;Imai S;Bass J
通讯作者：
Bass J
影响因子：
4.8
作者：
Moghadasian, MH;McManus, BM;Frohlich, JJ
通讯作者：
Frohlich, JJ