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Modulation of amyloid precursor protein cleavage by cellular sphingolipids
Naoya Sawamura1, Mihee Ko, Wenxin Yu
1Department of Dementia Research, National Institute for Longevity Sciences, 36-3 Gengo, Morioka, Obu, Aichi 474-8522, Japan.
The Journal of Biological Chemistry
|January 13, 2004
Summary
Sphingolipid deficiency increases amyloid-beta 42 secretion and soluble amyloid precursor protein alpha (sAPPalpha) by activating the MAPK/ERK pathway. These findings suggest sphingolipids, like cholesterol, influence Alzheimer
Area of Science:
- Cell Biology
- Neuroscience
- Biochemistry
Background:
- Lipid rafts, including cholesterol, influence beta-amyloid precursor protein (APP) processing.
- The role of sphingolipids in APP processing is not well understood.
Purpose of the Study:
- To investigate the impact of sphingolipid deficiency on APP processing.
- To explore the underlying mechanisms, including the MAPK/ERK pathway.
Main Methods:
- Utilized Chinese hamster ovary cells with inhibited sphingolipid biosynthesis.
- Employed a mutant LY-B cell strain deficient in serine palmitoyltransferase.
- Analyzed APP cleavage products, amyloid-beta secretion, and MAPK/ERK activity.
Main Results:
- Sphingolipid deficiency increased soluble APPalpha (sAPPalpha) and amyloid-beta 42 secretion.
- Beta-cleavage activity remained unchanged, while epsilon-cleavage decreased.
- Sphingolipid deficiency activated the MAPK/ERK pathway, which was reversed by PD98059.
Conclusions:
- Sphingolipids, in addition to cholesterol, modulate APP cleavage.
- Sphingolipid deficiency enhances sAPPalpha secretion via the MAPK/ERK pathway.
- These findings suggest a role for sphingolipids in Alzheimer's disease pathogenesis.