Human embryonic stem and induced pluripotent stem cell–derived neuroprogenitors (NPs) develop primary cilia. Ciliogenesis depends on the sphingolipid ceramide and its interaction with atypical PKC, both of which distribute to the primary cilium and the apicolateral cell membrane in NP rosettes.

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We present evidence that 5XFAD Alzheimer's disease model mice develop an age-dependent increase in antibodies against ceramide, suggesting involvement of autoimmunity against ceramide in Alzheimer's disease pathology. To test this, we increased serum anti-ceramide IgG (2-fold) by ceramide administration and analyzed amyloid plaque formation in 5XFAD mice. There were no differences in soluble or total amyloid-β levels. However, females receiving ceramide had increased plaque burden (number, area, and size) compared to controls. Ceramide-treated mice showed an increase of serum exosomes (up to 3-fold using Alix as marker), suggesting that systemic anti-ceramide IgG and exosome levels are correlated with enhanced plaque formation.

Cilia are important organelles formed by cell membrane protrusions; however, little is known about their regulation by membrane lipids. A novel, evolutionarily conserved activation mechanism for GSK3 by the sphingolipid (phyto)ceramide is characterized that is critical for ciliogenesis in Chlamydomonas and murine ependymal cells.