TY - JOUR
T1 - FAD mutations in presenilin-1 or amyloid precursor protein decrease the efficacy of a γ-secretase inhibitor
T2 - Evidence for direct involvement of PS1 in the γ-secretase cleavage complex
AU - Xia, Weiming
AU - Ostaszewski, Beth L.
AU - Taylor Kimberly, W. Taylor
AU - Rahmati, Talat
AU - Moore, Chad L.
AU - Wolfe, Michael S.
AU - Selkoe, Dennis J.
PY - 2000/12
Y1 - 2000/12
N2 - To investigate the mechanism of regulation of Aβ production by familial Alzheimer's disease linked presenilin 1 (PS1), we used a cell-free system that allows de novo Aβ generation to examine whether PS1 participates directly in the γ-secretase reaction. Optimal Aβ generation in vitro was achieved at mildly acidic pH and could be inhibited by the aspartyl protease inhibitor pepstalin A, consistent with the suggestion that γ-secretase is an aspartyl protease. Dominant negative mutations of the critical transmembrane aspartates in PS1 or full deletion of PS1 did not alter the maturation of APP in the secretory pathway. Instead, PS1 had a direct effect on the inhibition of Aβ production by a designed peptidomimetic inhibitor: the inhibition was significantly less effective in cells expressing FAD-causing mutations in either APP or PS1 than in cells expressing the wild-type proteins. Taken together, these findings suggest that PS1 participates physically in a complex with APP during the γ-secretase cleavage event.
AB - To investigate the mechanism of regulation of Aβ production by familial Alzheimer's disease linked presenilin 1 (PS1), we used a cell-free system that allows de novo Aβ generation to examine whether PS1 participates directly in the γ-secretase reaction. Optimal Aβ generation in vitro was achieved at mildly acidic pH and could be inhibited by the aspartyl protease inhibitor pepstalin A, consistent with the suggestion that γ-secretase is an aspartyl protease. Dominant negative mutations of the critical transmembrane aspartates in PS1 or full deletion of PS1 did not alter the maturation of APP in the secretory pathway. Instead, PS1 had a direct effect on the inhibition of Aβ production by a designed peptidomimetic inhibitor: the inhibition was significantly less effective in cells expressing FAD-causing mutations in either APP or PS1 than in cells expressing the wild-type proteins. Taken together, these findings suggest that PS1 participates physically in a complex with APP during the γ-secretase cleavage event.
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U2 - 10.1006/nbdi.2000.0322
DO - 10.1006/nbdi.2000.0322
M3 - Article
C2 - 11114265
AN - SCOPUS:0034523058
VL - 7
SP - 673
EP - 681
JO - Neurobiology of Disease
JF - Neurobiology of Disease
SN - 0969-9961
IS - 6
ER -