TY - JOUR
T1 - Lipid rafts play an important role in Aβ biogenesis by regulating the β-secretase pathway
AU - Tun, Han
AU - Marlow, Laura
AU - Pinnix, Inga
AU - Kinsey, Rachel
AU - Sambamurti, Kumar
PY - 2002
Y1 - 2002
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - Amyloid
KW - DIGs
KW - GPI-anchored protein
KW - Glycosylphosphatidylinositol
KW - Lipid rafts
KW - Secretase
KW - TIMs
UR - http://www.scopus.com/inward/record.url?scp=0036674082&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036674082&partnerID=8YFLogxK
U2 - 10.1007/s12031-002-0007-5
DO - 10.1007/s12031-002-0007-5
M3 - Article
C2 - 12212790
AN - SCOPUS:0036674082
SN - 0895-8696
VL - 19
SP - 31
EP - 35
JO - Journal of Molecular Neuroscience
JF - Journal of Molecular Neuroscience
IS - 1-2
ER -