Furber Kendra L, Lacombe R J Scott, Caine Sally, Thangaraj Merlin P, Read Stuart, Rosendahl Scott M, Bazinet Richard P, Popescu Bogdan F, Nazarali Adil J
College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada.
Department of Anatomy, Physiology and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
Neurochem Res. 2022 Mar;47(3):795-810. doi: 10.1007/s11064-021-03491-y. Epub 2021 Nov 24.
White matter degeneration in the central nervous system (CNS) has been correlated with a decline in cognitive function during aging. Ultrastructural examination of the aging human brain shows a loss of myelin, yet little is known about molecular and biochemical changes that lead to myelin degeneration. In this study, we investigate myelination across the lifespan in C57BL/6 mice using electron microscopy and Fourier transform infrared (FTIR) spectroscopic imaging to better understand the relationship between structural and biochemical changes in CNS white matter tracts. A decrease in the number of myelinated axons was associated with altered lipid profiles in the corpus callosum of aged mice. FTIR spectroscopic imaging revealed alterations in functional groups associated with phospholipids, including the lipid acyl, lipid ester and phosphate vibrations. Biochemical changes in white matter were observed prior to structural changes and most predominant in the anterior regions of the corpus callosum. This was supported by biochemical analysis of fatty acid composition that demonstrated an overall trend towards increased monounsaturated fatty acids and decreased polyunsaturated fatty acids with age. To further explore the molecular mechanisms underlying these biochemical alterations, gene expression profiles of lipid metabolism and oxidative stress pathways were investigated. A decrease in the expression of several genes involved in glutathione metabolism suggests that oxidative damage to lipids may contribute to age-related white matter degeneration.
中枢神经系统（CNS）中的白质退化与衰老过程中认知功能的下降有关。对衰老人类大脑的超微结构检查显示髓鞘丢失，但对于导致髓鞘退化的分子和生化变化知之甚少。在本研究中，我们使用电子显微镜和傅里叶变换红外（FTIR）光谱成像技术，研究了C57BL/6小鼠整个生命周期中的髓鞘形成情况，以更好地理解中枢神经系统白质束结构和生化变化之间的关系。老龄小鼠胼胝体中髓鞘轴突数量的减少与脂质谱的改变有关。FTIR光谱成像揭示了与磷脂相关的官能团的改变，包括脂质酰基、脂质酯和磷酸盐振动。在结构变化之前就观察到了白质的生化变化，且在胼胝体前部最为明显。脂肪酸组成的生化分析支持了这一点，该分析表明，随着年龄的增长，单不饱和脂肪酸总体呈增加趋势，多不饱和脂肪酸呈减少趋势。为了进一步探索这些生化改变背后的分子机制，我们研究了脂质代谢和氧化应激途径的基因表达谱。参与谷胱甘肽代谢的几个基因的表达下降表明，脂质的氧化损伤可能导致与年龄相关的白质退化。
