Expression and p75 neurotrophin receptor dependence of cholesterol synthetic enzymes in adult mouse brain
Expression and p75 neurotrophin receptor dependence of cholesterol synthetic enzymes in adult mouse brain
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DOI：
10.1016/j.neurobiolaging.2006.06.026
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发表时间：
2007-10-01
影响因子：
4.2
通讯作者：
Schor, Nina E.
中科院分区：
文献类型：
--
作者：
Korade, Zeljka;Mi, Zhiping;Schor, Nina E.
正常的大脑功能严重依赖于胆固醇。虽然胆固醇在成人大脑中局部合成，但胆固醇生成酶的精确解剖定位尚不清楚。在这里，我们表明，3-羟基-3-甲基戊二酰辅酶A还原酶（HMG-CoAred）和7-脱氢胆固醇还原酶（7 dhcred），第一个和最后一个酶，分别在胆固醇生物合成途径，共表达在整个成年小鼠大脑的神经元。共同定位最为突出。大脑皮层海马和胆碱能神经元由于成年海马和胆碱能神经元表达p75神经营养因子受体（p75 NTR），我们假设p75 NTR调节胆固醇生成酶的表达。用siRNA处理Neuro 2a神经母细胞瘤细胞或原代小脑培养物下调p75 NTR，并降低HMG-CoAred和7 dhcred的表达水平。具有p75 NTR差异表达的天然神经母细胞瘤细胞系差异表达7 dhcred; 7 dhcred表达与p75 NTR表达相关。这表明，在表达p75 NTR的细胞中，p75 NTR通过调节HMG-CoAred和7 dhcred的表达来调节胆固醇合成。胆固醇生成酶在成年神经元中的意外定位表明，至少有一些成年神经元保留了合成胆固醇的能力。(c)2006年爱思唯尔公司All rights reserved.
Normal brain function depends critically on cholesterol. Although cholesterol is synthesized locally in the adult brain, the precise anatomical localization of cholesterogenic enzymes is not known. Here we show that 3-hydroxy-3-inethylglutaryl-coenzyme A reductase (HMG-CoAred) and 7-dehydrocholesterol reductase (7dhcred), the first and last enzymes, respectively, in the cholesterol biosynthesis pathway, are co-expressed in neurons throughout adult murine brain. Co-localization is most prominent. in cortical, hippocampal, and cholinergic neurons. Since adult hippocampal and cholinoergic neurons express p75 neurotrophin receptors (p75NTR) we hypothesized that p75NTR regulates expression of cholesterogenic enzymes. Treatment of Neuro2a neuroblastoma cells or primary cerebellar cultures with siRNA downregulates p75NTR and decreases the expression level of HMG-CoAred and 7dhcred. Native nuroblastoma cell lines with differential expression of p75NTR differentially express 7dhcred; 7dhcred expression correlates with p75NTR expression. This suggests that, in p75NTR-expressing cells, p75NTR regulates cholesterol synthesis through regulation of HMG-CoAred and 7dhcred expression. The unexpected localization of cholesterogenic enzymes in adult neurons suggests that at least some adult neurons retain the ability to synthesize cholesterol. (c) 2006 Elsevier Inc. All rights reserved.