期刊
NEUROCHEMICAL RESEARCH
卷 25, 期 2, 页码 247-255出版社
KLUWER ACADEMIC/PLENUM PUBL
DOI: 10.1023/A:1007527721160
关键词
amyloid beta peptide; Alzheimer's disease; insulin degrading enzyme; Dutch variant
Insulin degrading enzyme (IDE) is a metalloprotease that has been involved in amyloid beta peptide (A beta) degradation in the brain. We analyzed the ability of human brain soluble fraction to degrade A beta analogs 1-40, 1-42 and the Dutch variant 1-40Q at physiological concentrations (1 nM). The rate of synthetic I-125-A beta degradation was similar among the A beta analogs, as demonstrated by trichloroacetic acid precipitation and SDS-PAGE. A 110 kDa protein, corresponding to the molecular mass of IDE, was affinity labeled with either I-125-insulin, I-125-A beta 1-40 or I-125-A beta 1-42 and both A beta degradation and cross-linking were specifically inhibited by an excess of each peptide. Sensitivity to inhibitors was consistent with the reported inhibitor profile of IDE. Taken together, these results suggested that the degradation of A beta analogs was due to IDE or a closely related protease. The apparent Km, as determined using partially purified IDE from rat liver, were 2.2 +/- 0.4, 2.0 +/- 0.1 and 2.3 +/- 0.3 mu M for A beta 1-40, A beta 1-42 and A beta 1-40Q, respectively. Comparison of IDE activity from seven AD brain cytosolic fractions and six age-matched controls revealed a significant decrease in A beta degrading activity in the first group, supporting the hypothesis that a reduced IDE activity may contribute to A beta accumulation in the brain.
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