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Loss of ceramide synthase 2 activity, necessary for myelin biosynthesis, precedes tau pathology in the cortical pathogenesis of Alzheimer's disease

Journal Article


Abstract


  • The anatomical progression of neurofibrillary tangle pathology throughout Alzheimer's disease (AD) pathogenesis runs inverse to the pattern of developmental myelination, with the disease preferentially affecting thinly myelinated regions. Myelin is comprised 80% of lipids, and the prototypical myelin lipids, galactosylceramide, and sulfatide are critical for neurological function. We observed severe depletion of galactosylceramide and sulfatide in AD brain tissue, which can be traced metabolically to the loss of their biosynthetic precursor, very long chain ceramide. The synthesis of very long chain ceramides is catalyzed by ceramide synthase 2 (CERS2). We demonstrate a significant reduction in CERS2 activity as early as Braak stage I/II in temporal cortex, and Braak stage III/IV in hippocampus and frontal cortex, indicating that loss of myelin-specific ceramide synthase activity precedes neurofibrillary tangle pathology in cortical regions. These findings open a new vista on AD pathogenesis by demonstrating a defect in myelin lipid biosynthesis at the preclinical stages of the disease. We posit that, over time, this defect contributes significantly to myelin deterioration, synaptic dysfunction, and neurological decline.

Authors


  •   Couttas, Timothy A. (external author)
  •   Kain, Nupur (external author)
  •   Suchowerska, Alexandra (external author)
  •   Quek, Lake Ee (external author)
  •   Turner, Nigel (external author)
  •   Fath, Thomas (external author)
  •   Garner, Brett
  •   Don, Anthony S. (external author)

Publication Date


  • 2016

Citation


  • Couttas, T. A., Kain, N., Suchowerska, A. K., Quek, L., Turner, N., Fath, T., Garner, B. & Don, A. S. (2016). Loss of ceramide synthase 2 activity, necessary for myelin biosynthesis, precedes tau pathology in the cortical pathogenesis of Alzheimer's disease. Neurobiology of Aging, 43 89-100.

Scopus Eid


  • 2-s2.0-84966716451

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/3799

Number Of Pages


  • 11

Start Page


  • 89

End Page


  • 100

Volume


  • 43

Abstract


  • The anatomical progression of neurofibrillary tangle pathology throughout Alzheimer's disease (AD) pathogenesis runs inverse to the pattern of developmental myelination, with the disease preferentially affecting thinly myelinated regions. Myelin is comprised 80% of lipids, and the prototypical myelin lipids, galactosylceramide, and sulfatide are critical for neurological function. We observed severe depletion of galactosylceramide and sulfatide in AD brain tissue, which can be traced metabolically to the loss of their biosynthetic precursor, very long chain ceramide. The synthesis of very long chain ceramides is catalyzed by ceramide synthase 2 (CERS2). We demonstrate a significant reduction in CERS2 activity as early as Braak stage I/II in temporal cortex, and Braak stage III/IV in hippocampus and frontal cortex, indicating that loss of myelin-specific ceramide synthase activity precedes neurofibrillary tangle pathology in cortical regions. These findings open a new vista on AD pathogenesis by demonstrating a defect in myelin lipid biosynthesis at the preclinical stages of the disease. We posit that, over time, this defect contributes significantly to myelin deterioration, synaptic dysfunction, and neurological decline.

Authors


  •   Couttas, Timothy A. (external author)
  •   Kain, Nupur (external author)
  •   Suchowerska, Alexandra (external author)
  •   Quek, Lake Ee (external author)
  •   Turner, Nigel (external author)
  •   Fath, Thomas (external author)
  •   Garner, Brett
  •   Don, Anthony S. (external author)

Publication Date


  • 2016

Citation


  • Couttas, T. A., Kain, N., Suchowerska, A. K., Quek, L., Turner, N., Fath, T., Garner, B. & Don, A. S. (2016). Loss of ceramide synthase 2 activity, necessary for myelin biosynthesis, precedes tau pathology in the cortical pathogenesis of Alzheimer's disease. Neurobiology of Aging, 43 89-100.

Scopus Eid


  • 2-s2.0-84966716451

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/3799

Number Of Pages


  • 11

Start Page


  • 89

End Page


  • 100

Volume


  • 43