Université Catholique de Louvain, Brussels, Belgium; Institute of Neuroscience, Brussels, Belgium.
EMBO Mol Med. 2013 Apr;5(4):608-25. doi: 10.1002/emmm.201202215.
Perturbation of lipid metabolism favours progression of Alzheimer disease, in which processing of Amyloid Precursor Protein (APP) has important implications. APP cleavage is tightly regulated by cholesterol and APP fragments regulate lipid homeostasis. Here, we investigated whether up or down regulation of full-length APP expression affected neuronal lipid metabolism. Expression of APP decreased HMG-CoA reductase (HMGCR)-mediated cholesterol biosynthesis and SREBP mRNA levels, while its down regulation had opposite effects. APP and SREBP1 co-immunoprecipitated and co-localized in the Golgi. This interaction prevented Site-2 protease-mediated processing of SREBP1, leading to inhibition of transcription of its target genes. A GXXXG motif in APP sequence was critical for regulation of HMGCR expression. In astrocytes, APP and SREBP1 did not interact nor did APP affect cholesterol biosynthesis. Neuronal expression of APP decreased both HMGCR and cholesterol 24-hydroxylase mRNA levels and consequently cholesterol turnover, leading to inhibition of neuronal activity, which was rescued by geranylgeraniol, generated in the mevalonate pathway, in both APP expressing and mevastatin treated neurons. We conclude that APP controls cholesterol turnover needed for neuronal activity.
脂质代谢的紊乱有利于阿尔茨海默病的进展，其中淀粉样前体蛋白（APP）的加工具有重要意义。APP 的切割受到胆固醇的严格调控，APP 片段调节脂质稳态。在这里，我们研究了全长 APP 表达的上调或下调是否会影响神经元的脂质代谢。APP 的表达降低了 HMG-CoA 还原酶（HMGCR）介导的胆固醇生物合成和 SREBP mRNA 水平，而下调则有相反的效果。APP 和 SREBP1 在高尔基体中共免疫沉淀和共定位。这种相互作用阻止了 Site-2 蛋白酶对 SREBP1 的加工，从而抑制了其靶基因的转录。APP 序列中的 GXXXG 基序对 HMGCR 表达的调控至关重要。在星形胶质细胞中，APP 和 SREBP1 不相互作用，APP 也不影响胆固醇生物合成。神经元表达的 APP 降低了 HMGCR 和胆固醇 24-羟化酶的 mRNA 水平，进而降低了胆固醇周转率，导致神经元活动抑制，而在 APP 表达和甲羟戊酸途径中产生的香叶基香叶醇都可以挽救这种抑制作用。我们得出的结论是，APP 控制着神经元活动所需的胆固醇周转率。
