神经退行性变
生物
海马体
疾病
胆固醇
内分泌学
ABCA1
海马结构
阿尔茨海默病
医学
内科学
NPC1
细胞生物学
神经科学
淀粉样前体蛋白
生物化学
基因
运输机
内体
细胞内
作者
Fathia Djelti,Jérôme Braudeau,Eloïse Hudry,Marc Dhénain,Jennifer Varin,Ivan Bièche,Catherine Marquer,Farah Chali,Sophie Ayciriex,Nicolas Auzeil,Sandro Alves,Dominique Langui,Marie‐Claude Potier,Olivier Laprévôte,Michel Vidaud,Charles Duyckaerts,Richard Miles,Patrick Aubourg,Nathalie Cartier
出处
期刊:Brain
[Oxford University Press]
日期:2015-07-02
卷期号:138 (8): 2383-2398
被引量:160
摘要
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 β-C-terminal fragment and amyloid-β 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-β 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.
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