TY - JOUR
T1 - Amyloid-β peptide levels in brain are inversely correlated with insulysin activity levels in vivo
AU - Miller, Bonnie C.
AU - Eckman, Elizabeth A.
AU - Sambamurti, Kumar
AU - Dobbs, Nicole
AU - Martin Chow, K.
AU - Eckman, Christopher B.
AU - Hersh, Louis B.
AU - Thiele, Dwain L
PY - 2003/5/13
Y1 - 2003/5/13
N2 - Factors that elevate amyloid-β (Aβ) peptide levels are associated with an increased risk for Alzheimer's disease. Insulysin has been identified as one of several proteases potentially involved in Aβ degradation based on its hydrolysis of Aβ peptides in vitro. In this study, in vivo levels of brain Aβ40 and Aβ42 peptides were found to be increased significantly (1.6- and 1.4-fold, respectively) in an insulysin-deficient gene-trap mouse model. A 6-fold increase in the level of the γ-secretase-generated C-terminal fragment of the Aβ precursor protein in the insulysin-deficient mouse also was found. In mice heterozygous for the insulysin gene trap, in which insulysin activity levels were decreased ≊50%, brain A> peptides were increased to levels intermediate between those in wild-type mice and homozygous insulysin gene-trap mice that had no detectable insulysin activity. These findings indicate that there is an inverse correlation between in vivo insulysin activity levels and brain A> peptide levels and suggest that modulation of insulysin activity may alter the risk for Alzheimer's disease.
AB - Factors that elevate amyloid-β (Aβ) peptide levels are associated with an increased risk for Alzheimer's disease. Insulysin has been identified as one of several proteases potentially involved in Aβ degradation based on its hydrolysis of Aβ peptides in vitro. In this study, in vivo levels of brain Aβ40 and Aβ42 peptides were found to be increased significantly (1.6- and 1.4-fold, respectively) in an insulysin-deficient gene-trap mouse model. A 6-fold increase in the level of the γ-secretase-generated C-terminal fragment of the Aβ precursor protein in the insulysin-deficient mouse also was found. In mice heterozygous for the insulysin gene trap, in which insulysin activity levels were decreased ≊50%, brain A> peptides were increased to levels intermediate between those in wild-type mice and homozygous insulysin gene-trap mice that had no detectable insulysin activity. These findings indicate that there is an inverse correlation between in vivo insulysin activity levels and brain A> peptide levels and suggest that modulation of insulysin activity may alter the risk for Alzheimer's disease.
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U2 - 10.1073/pnas.1031520100
DO - 10.1073/pnas.1031520100
M3 - Article
C2 - 12732730
AN - SCOPUS:0037947406
SN - 0027-8424
VL - 100
SP - 6221
EP - 6226
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 10
ER -