Lipid rafts play an important role in Aβ biogenesis by regulating the β-secretase pathway

Han W Tun, Laura Marlow, Inga Pinnix, Rachel Kinsey, Kumar Sambamurti

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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 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.

Original languageEnglish (US)
Pages (from-to)31-35
Number of pages5
JournalJournal of Molecular Neuroscience
Volume19
Issue number1-2
StatePublished - Aug 2002

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Tun, HW, Marlow, L, Pinnix, I, Kinsey, R & Sambamurti, K 2002, 'Lipid rafts play an important role in Aβ biogenesis by regulating the β-secretase pathway', Journal of Molecular Neuroscience, vol. 19, no. 1-2, pp. 31-35.