CYP46A1 inhibition, brain cholesterol accumulation and neurodegeneration pave the way for Alzheimer's disease
CYP46A1 inhibition, brain cholesterol accumulation and neurodegeneration pave the way for Alzheimer's disease
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DOI：
10.1093/brain/awv166
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发表时间：
2015-08-01
期刊：
影响因子：
14.5
通讯作者：
Cartier, Nathalie
中科院分区：
文献类型：
--
作者：
Djelti, Fathia;Braudeau, Jerome;Cartier, Nathalie
在包括阿尔茨海默病、帕金森病和亨廷顿病在内的几种神经退行性疾病中，已经怀疑或观察到神经元胆固醇稳态的失调。然而，尚未证明体内神经元中胆固醇丰度的增加是否有助于神经变性。为了解决这个问题，我们使用RNA干扰方法来抑制胆固醇24-羟化酶的表达，Cyp 46 a1基因编码的，在正常小鼠的海马。胆固醇24-羟化酶控制胆固醇从脑中流出，从而在调节脑胆固醇稳态中起主要作用。我们使用腺相关病毒载体编码短发夹RNA针对小鼠Cyp 46 a1 mRNA的表达降低Cyp 46 a1基因在正常小鼠海马神经元的表达。这增加了神经元中的胆固醇浓度，随后由于神经元凋亡导致认知缺陷和海马萎缩。在神经元死亡之前，淀粉样蛋白前体向脂筏的募集增强，导致β-C-末端片段和淀粉样β肽的产生。还观察到tau蛋白的异常磷酸化和内质网应激。在阿尔茨海默病的APP 23小鼠模型中，Cyp 46 a1表达抑制后淀粉样β肽的丰度增加，神经元死亡比正常小鼠更普遍。总之，这些结果表明，脑内神经元胆固醇的增加可能有助于诱导和/或加重阿尔茨海默病。
Abnormalities in neuronal cholesterol homeostasis have been suspected or observed in several neurodegenerative disorders including Alzheimer's disease, Parkinson's disease and Huntington's disease. However, it has not been demonstrated whether an increased abundance of cholesterol in neurons in vivo contributes to neurodegeneration. To address this issue, we used RNA interference methodology to inhibit the expression of cholesterol 24-hydroxylase, encoded by the Cyp46a1 gene, in the hippocampus of normal mice. Cholesterol 24-hydroxylase controls cholesterol efflux from the brain and thereby plays a major role in regulating brain cholesterol homeostasis. We used an adeno-associated virus vector encoding short hairpin RNA directed against the mouse Cyp46a1 mRNA to decrease the expression of the Cyp46a1 gene in hippocampal neurons of normal mice. This increased the cholesterol concentration in neurons, followed by cognitive deficits and hippocampal atrophy due to apoptotic neuronal death. Prior to neuronal death, the recruitment of the amyloid protein precursor to lipid rafts was enhanced leading to the production of beta-C-terminal fragment and amyloid-beta peptides. Abnormal phosphorylation of tau and endoplasmic reticulum stress were also observed. In the APP23 mouse model of Alzheimer's disease, the abundance of amyloid-beta peptides increased following inhibition of Cyp46a1 expression, and neuronal death was more widespread than in normal mice. Altogether, these results suggest that increased amounts of neuronal cholesterol within the brain may contribute to inducing and/or aggravating Alzheimer's disease.