Abstract
The Alzheimer’s amyloid β protein (Aβ) precursor (APP) is proteolytically cleaved by β-secretase to N- and C-terminal fragments sAPPβ and CTFβ, respectively. Subsequently, CTFβ is cleaved by γ-secretase to generate Aβ. We previously showed that the levels of secreted Aβ and sAPPβ were significantly reduced upon removal of glycosylphosphatidylinositol (GPI)-anchored proteins from either primary brain cells or Chinese hamster ovary cultures. The results indicated that GPI-anchored proteins facilitated β-secretase activity. In this report, we strengthen the previous findings by demonstrating that CTFβ, like a sAPPβ, is also reduced upon removal of GPI-anchored proteins and that sAPPβ does not accumulate in an intracellular compartment. This facilitation pathway does not appear to be important for the processing of a disease-linked mutant form of APP (670NL), known to be a superior β-secretase substrate. A novel aspartyl protease, BACE, responsible for β-secretase activity in the brain is not GPI-anchored. However, BACE in brain membranes accumulate in lipid rafts, a compartment marked by the accumulation of GPI-anchored proteins. This finding is consistent with the hypothesis that BACE interacts with GPI-anchored proteins that facilitate its activity possibly by chaperoning it into lipid rafts.
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Tun, H., Marlow, L., Pinnix, I. et al. Lipid rafts play an important role in Aβ biogenesis by regulating the β-secretase pathway. J Mol Neurosci 19, 31–35 (2002). https://doi.org/10.1007/s12031-002-0007-5
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DOI: https://doi.org/10.1007/s12031-002-0007-5