Marquer Catherine, Laine Jeanne, Dauphinot Luce, Hanbouch Linda, Lemercier-Neuillet Camille, Pierrot Nathalie, Bossers Koen, Le Mickael, Corlier Fabian, Benstaali Caroline, Saudou Frédéric, Thinakaran Gopal, Cartier Nathalie, Octave Jean-Noël, Duyckaerts Charles, Potier Marie-Claude
Sorbonne Universités, UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, 75013 Paris, France.
Mol Neurodegener. 2014 Dec 18;9:60. doi: 10.1186/1750-1326-9-60.
It is suspected that excess of brain cholesterol plays a role in Alzheimer's disease (AD). Membrane-associated cholesterol was shown to be increased in the brain of individuals with sporadic AD and to correlate with the severity of the disease. We hypothesized that an increase of membrane cholesterol could trigger sporadic AD early phenotypes.
We thus acutely loaded the plasma membrane of cultured neurons with cholesterol to reach the 30% increase observed in AD brains. We found changes in gene expression profiles that are reminiscent of early AD stages. We also observed early AD cellular phenotypes. Indeed we found enlarged and aggregated early endosomes using confocal and electron microscopy after immunocytochemistry. In addition amyloid precursor protein vesicular transport was inhibited in neuronal processes, as seen by live-imaging. Finally transient membrane cholesterol loading lead to significantly increased amyloid-β42 secretion.
Membrane cholesterol increase in cultured neurons reproduces most early AD changes and could thus be a relevant model for deciphering AD mechanisms and identifying new therapeutic targets.
据推测，大脑中胆固醇过量在阿尔茨海默病（AD）中起作用。在散发性AD患者大脑中，膜相关胆固醇增加，且与疾病严重程度相关。我们假设膜胆固醇增加可能引发散发性AD的早期表型。
因此，我们用胆固醇急性加载培养神经元的质膜，使其达到AD大脑中观察到的30%的增加量。我们发现基因表达谱的变化让人联想到AD早期阶段。我们还观察到了AD早期细胞表型。实际上，免疫细胞化学后通过共聚焦和电子显微镜观察发现早期内体增大并聚集。此外，实时成像显示神经元突起中淀粉样前体蛋白囊泡运输受到抑制。最后，短暂的膜胆固醇加载导致淀粉样β42分泌显著增加。
培养神经元中膜胆固醇增加重现了大多数AD早期变化，因此可能是解读AD机制和识别新治疗靶点的相关模型。
