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

Timothy A. Couttas, Nupur Kain, Alexandra K. Suchowerska, Lake-Ee Quek, Nigel Turner, Thomas Fath, Brett Garner, Anthony S. Don*

*Corresponding author for this work

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)89-100
Number of pages12
JournalNeurobiology of Aging
Volume43
DOIs
Publication statusPublished - 1 Jul 2016
Externally publishedYes

Keywords

  • Alzheimer's disease
  • Ceramide
  • Ceramide synthase 2
  • Galactosylceramide
  • Myelin
  • Sulfatide

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