Increased expression of cholesterol 24S-hydroxylase results in disruption of glial glutamate transporter EAAT2 association with lipid rafts: a potential role in Alzheimer's disease.
Increased expression of cholesterol 24S-hydroxylase results in disruption of glial glutamate transporter EAAT2 association with lipid rafts: a potential role in Alzheimer's disease.
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DOI：
10.1111/j.1471-4159.2010.06661.x
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发表时间：
2010-05
影响因子：
4.7
通讯作者：
Lin CL
中科院分区：
文献类型：
--
作者：
Tian G;Kong Q;Lai L;Ray-Chaudhury A;Lin CL
胶质细胞谷氨酸转运蛋白 EAAT2 是谷氨酸清除的主要介质，可终止谷氨酸介导的神经传递。据报道，阿尔茨海默病 (AD) 患者的大脑中存在 EAAT2 和相关谷氨酸摄取功能的丧失。我们之前报道过 EAAT2 与质膜的脂筏微区相关。在本研究中，我们证明 EAAT2 与脂筏的关联在 AD 大脑中被破坏。这种异常不是神经元变性、氧化应激或β淀粉样蛋白毒性的结果。在AD大脑中，胆固醇24S-羟化酶（CYP46）是维持大脑胆固醇稳态的关键酶，在星形胶质细胞中显着增加，但在神经元中减少。我们证明，原代星形胶质细胞中 CYP46 表达增加会导致膜胆固醇水平降低，并导致 EAAT2 从脂筏解离以及 EAAT2 和相关谷氨酸摄取功能的丧失。这些结果表明，胆固醇代谢紊乱可能导致 AD 中 EAAT2 的缺失。
The glial glutamate transporter EAAT2 is the major mediator of glutamate clearance that terminates glutamate-mediated neurotransmission. Loss of EAAT2 and associated glutamate uptake function has been reported in the brains of patients with Alzheimer’s disease (AD). We previously reported that EAAT2 is associated with lipid raft microdomains of the plasma membrane. In the present study, we demonstrated that association of EAAT2 with lipid rafts is disrupted in AD brains. This abnormality is not a consequence of neuron degeneration, oxidative stress, or amyloid beta toxicity. In AD brains, cholesterol 24S-hydroxylase (CYP46), a key enzyme in maintenance of cholesterol homeostasis in the brain, is markedly increased in astrocytes but decreased in neurons. We demonstrated that increased expression of CYP46 in primary astrocytes results in a reduction of membrane cholesterol levels and leads to the dissociation of EAAT2 from lipid rafts and the loss of EAAT2 and associated glutamate uptake function. These results suggest that a disturbance of cholesterol metabolism may contribute to loss of EAAT2 in AD.
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