Partial Amelioration of Peripheral and Central Symptoms of Huntington's Disease via Modulation of Lipid Metabolism.
Partial Amelioration of Peripheral and Central Symptoms of Huntington's Disease via Modulation of Lipid Metabolism.
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DOI：
10.3233/jhd-150181
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Cepeda C
中科院分区：
文献类型：
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作者：
Chen JY;Tran C;Hwang L;Deng G;Jung ME;Faull KF;Levine MS;Cepeda C
亨廷顿氏病（HD）是一种致命的遗传性神经退行性疾病，其特征在于不可控制的舞蹈样运动，以及认知缺陷和情绪变化。HD的一个特征是先于神经系统症状的代谢紊乱。此外，脑胆固醇合成显著减少，这可能会阻碍突触传递。在HD的R6/2小鼠模型中检查作为治疗干预的潜在靶点的脂质代谢的改变。体外电生理记录检查了胆固醇修饰药物的急性作用。此外，在正常饲料或生酮饲料（KD）饲养的有症状R6/2小鼠和同窝对照小鼠中，检查了行为测试、对突触活动的影响以及胆固醇和β-羟基丁酸酮（BHB）的循环和脑组织浓度测量值。有症状的R6/2小鼠纹状体中型多刺神经元（MSN）的全细胞电压钳记录显示，与同窝对照组相比，自发抑制性突触后电流（sIPSC）的频率增加。在胆固醇中孵育切片降低了大幅度sIPSC的频率。添加BHB或肝脏X受体（LXR）激动剂T0901317降低了sIPSC的频率和振幅。令人惊讶的是，在辛伐他汀中孵育以降低胆固醇水平也降低了sIPSC的频率。喂食KD的HD小鼠比喂食常规饮食的小鼠体重减轻得更缓慢，在开阔场地表现更好，刻板印象更少，大脑胆固醇水平更低。脂质代谢是HD治疗干预的潜在靶点。急性改变大脑中的胆固醇或酮水平可以部分挽救突触改变，KD可以防止体重减轻并改善一些行为异常。
Huntington’s disease (HD) is a fatal, inherited neurodegenerative disorder characterized by uncontrollable dance-like movements, as well as cognitive deficits and mood changes. A feature of HD is a metabolic disturbance that precedes neurological symptoms. In addition, brain cholesterol synthesis is significantly reduced, which could hamper synaptic transmission. Alterations in lipid metabolism as a potential target for therapeutic intervention in the R6/2 mouse model of HD were examined. Electrophysiological recordings in vitro examined the acute effects of cholesterol-modifying drugs. In addition, behavioral testing, effects on synaptic activity, and measurements of circulating and brain tissue concentrations of cholesterol and the ketone β-hydroxybutyrate (BHB), were examined in symptomatic R6/2 mice and littermate controls raised on normal chow or a ketogenic diet (KD). Whole-cell voltage clamp recordings of striatal medium-sized spiny neurons (MSNs) from symptomatic R6/2 mice showed increased frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) compared with littermate controls. Incubation of slices in cholesterol reduced the frequency of large-amplitude sIPSCs. Addition of BHB or the Liver X Receptor (LXR) agonist T0901317 reduced the frequency and amplitude of sIPSCs. Surprisingly, incubation in simvastatin to reduce cholesterol levels also decreased the frequency of sIPSCs. HD mice fed the KD lost weight more gradually, performed better in an open field, had fewer stereotypies and lower brain levels of cholesterol than mice fed a regular diet. Lipid metabolism represents a potential target for therapeutic intervention in HD. Modifying cholesterol or ketone levels acutely in the brain can partially rescue synaptic alterations, and the KD can prevent weight loss and improve some behavioral abnormalities.