Brain cholesterol turnover required for geranylgeraniol production and learning in mice
Brain cholesterol turnover required for geranylgeraniol production and learning in mice
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DOI：
10.1073/pnas.0600316103
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发表时间：
2006-03-07
影响因子：
11.1
通讯作者：
Russell, DW
中科院分区：
文献类型：
--
作者：
Kotti, TJ;Ramirez, DMO;Russell, DW
甲氧戊酸途径产生胆固醇和非甾醇类异戊二烯，如香叶基香叶醇。在大脑中，一小部分胆固醇在神经元中被胆固醇24-羟基酶代谢，这种消耗激活了甲氧戊酸途径。缺乏24-羟基酶的小鼠的大脑排泄胆固醇的速度较慢，该组织通过抑制甲氧戊酸途径进行补偿。在这里，我们报告说，这种压抑导致学习缺陷。24-羟基酶基因敲除小鼠在空间、联想和运动学习以及海马长时程增强(LTP)方面表现出严重的缺陷。用甲氧戊酸途径的抑制剂(他汀类药物)急性治疗野生型海马片也会损害LTP。他汀类药物治疗和24-羟基酶基因消除对LTIP的影响可被香叶醇处理20分钟逆转，但不能被胆固醇逆转。我们的结论是，大脑中的胆固醇转换激活了甲氧戊酸途径，在一小部分神经元中持续产生香叶香叶醇是LTP和学习所必需的。
The mevalonate pathway produces cholesterol and nonsterol isoprenoids, such as geranylgeraniol. In the brain, a fraction of cholesterol is metabolized in neurons by the enzyme cholesterol 24-hydroxylase, and this depletion activates the mevalonate pathway. Brains from mice lacking 24-hydroxylase excrete cholesterol more slowly, and the tissue compensates by suppressing the mevalonate pathway. Here we report that this suppression causes a defect in learning. 24-Hydroxylase knockout mice exhibit severe deficiencies in spatial, associative, and motor learning, and in hippocampal long-term potentiation (LTP). Acute treatment of wild-type hippocampal slices with an inhibitor of the mevalonate pathway (a statin) also impairs LTP. The effects of statin treatment and genetic elimination of 24-hydroxylase on LTIP are reversed by a 20-min treatment with geranylgeraniol but not by cholesterol. We conclude that cholesterol turnover in brain activates the mevalonate pathway and that a constant production of geranylgeraniol in a small subset of neurons is required for LTP and learning.