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Biochemical Alterations in White Matter Tracts of the Aging Mouse Brain Revealed by FTIR Spectroscopy Imaging

Abstract

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.

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Data and materials will be made available upon request.

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Acknowledgements

The authors wish to thank LaRhonda Sobchishin at the Western College of Veterinary Medicine Imaging Center, University of Saskatchewan for technical assistance with electron microscopy.

Funding

This work was supported by a Collaborative Innovation Development Grant from the Saskatchewan Health Research Foundation [Grant #3398] and funding from the Saskatchewan Flax Development Commission. KLF was the recipient of an endMS Postdoctoral Fellowship and MPT was a recipient of an endMS Doctoral Studentship Award from the Multiple Sclerosis Society of Canada. KLF was also a Fellow in the CIHR ‘Training in Health Research using Synchrotron Techniques’ program at the University of Saskatchewan.

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KLF, BFP and AJN conceived the overall design and were responsible for funding acquisition. KLF contributed to methodology, data collection, formal analysis and visualization for Figs. 17; SJSL and RPB contributed to methodology, data collection and formal analysis of Fig. 6; SC contributed to formal analysis and visualization of Fig. 25; SR and SMR contributed to methodology and data collection for Figs. 25; and MPT contributed to methodology and data collection for Figs. 1 and 7. KLF drafted original manuscript. SJSL, SC, BPB and BFP provided critical review and editing. All authors read and approved the final manuscript.

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Correspondence to Kendra L. Furber.

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All animal procedures performed were in accordance with the institutional ethical standards and adhered to the Canadian Council on Animal Care guidelines.

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Dr. A. J. Nazarali passed away on April 27, 2017.

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Furber, K.L., Lacombe, R.J.S., Caine, S. et al. Biochemical Alterations in White Matter Tracts of the Aging Mouse Brain Revealed by FTIR Spectroscopy Imaging. Neurochem Res 47, 795–810 (2022). https://doi.org/10.1007/s11064-021-03491-y

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  • DOI: https://doi.org/10.1007/s11064-021-03491-y

Keywords

  • Aging
  • Myelin
  • Corpus callosum
  • FTIR spectroscopy imaging
  • Phospholipid
  • Lipid metabolism
  • Oxidative stress