Lipid rafts play an important role in A beta biogenesis by regulating the beta-secretase pathway.
The Alzheimer's amyloid beta protein (A beta) precursor (APP) is proteolytically cleaved by beta-secretase to N- and C-terminal fragments sAPPbeta and CTFbeta, respectively. Subsequently, CTFbeta is cleaved by gamma-secretase to generate A beta. We previously showed that the levels of secreted A beta and sAPPbeta 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 beta-secretase activity. In this report, we strengthen the previous findings by demonstrating that CTFbeta, like sAPPbeta, is also reduced upon removal of GPI-anchored proteins and that sAPPbeta 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 beta-secretase substrate. A novel aspartyl protease, BACE, responsible for beta-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.
Tun
Han
H
Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Marlow
Laura
L
Pinnix
Inga
I
Kinsey
Rachel
R
Sambamurti
Kumar
K
D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D010450:Endopeptidases / Q000378:metabolism*; D017261:Glycosylphosphatidylinositols / Q000378:metabolism*; D006168:Guinea Pigs; D006801:Humans; D021962:Membrane Microdomains / Q000201:enzymology / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D017261:Glycosylphosphatidylinositols; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509284:BACE2 protein, human; C509280:BACE1 protein, human