Department of Pharmacology, Campus Riedberg, Biocenter Niederursel, University of Frankfurt, Max-von-Laue-St. 9, 60438 Frankfurt, Germany.
Mol Neurobiol. 2012 Aug;46(1):179-85. doi: 10.1007/s12035-012-8285-6. Epub 2012 Jun 13.
The mevalonate/isoprenoids/cholesterol pathway has a fundamental role in the brain. Increasing age could be associated with specific changes in mevalonate downstream products. Other than age differences in brain cholesterol and dolichol levels, there has been little if any evidence on the short-chain isoprenoids farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP), as well as downstream lipid products. The purpose of the present study was to determine whether brain levels of FPP, GGPP and sterol precursors and metabolites would be altered in aged mice (23 months) as compared to middle-aged mice (12 months) and young mice (3 months). FPP and GGPP levels were found to be significantly higher in brain homogenates of 23-months-old mice. The ratio of FPP to GGPP did not differ among the three age groups suggesting that increasing age does not alter the relative distribution of the two isoprenoids. Gene expression of FPP synthase and GGPP synthase did not differ among the three age groups. Gene expression of HMG-CoA reductase was significantly increased with age but in contrast gene expression of squalene synthase was reduced with increasing age. Levels of squalene, lanosterol and lathosterol did not differ among the three age groups. Desmosterol and 7-dehydroxycholesterol, which are direct precursors in the final step of cholesterol biosynthesis were significantly lower in brains of aged mice. Levels of cholesterol and its metabolites 24S- and 25S-hydroxycholesterol were similar in all three age groups. Our novel find ings on increased FPP and GGPP levels in brains of aged mice may impact on protein prenylation and contribute to neuronal dysfunction observed in aging and certain neurodegenerative diseases.
甲羟戊酸/异戊烯醇/胆固醇途径在大脑中具有重要作用。随着年龄的增长，甲羟戊酸下游产物可能会发生特定变化。除了大脑胆固醇和鲨烯醇水平在年龄上的差异外，关于短链异戊烯焦磷酸（FPP）和法尼基焦磷酸（GGPP）以及下游脂质产物，几乎没有证据。本研究的目的是确定与中年（12 个月）和年轻（3 个月）小鼠相比，老年（23 个月）小鼠大脑中的 FPP、GGPP 和固醇前体及代谢物水平是否会发生改变。结果发现，23 个月大的老鼠的大脑匀浆中的 FPP 和 GGPP 水平明显更高。三个年龄组之间 FPP 与 GGPP 的比值没有差异，这表明随着年龄的增长，两种异戊烯的相对分布并没有改变。FPP 合酶和 GGPP 合酶的基因表达在三个年龄组之间没有差异。HMG-CoA 还原酶的基因表达随年龄的增长而显著增加，但相反，鲨烯合酶的基因表达随年龄的增长而降低。三个年龄组之间的角鲨烯、羊毛甾醇和豆甾醇水平没有差异。在老年小鼠的大脑中，直接参与胆固醇生物合成最后一步的甾醇desmosterol 和 7-脱氢胆固醇水平显著降低。胆固醇及其代谢物 24S-和 25S-羟基胆固醇在所有三个年龄组中的水平相似。我们在老年小鼠大脑中发现的 FPP 和 GGPP 水平增加的新发现可能会影响蛋白质的prenylation，并导致衰老和某些神经退行性疾病中观察到的神经元功能障碍。
