TY - JOUR
T1 - Decreased catalytic activity of the insulin-degrading enzyme in chromosome 10-linked Alzheimer disease families
AU - Kim, Minji
AU - Hersh, Louis B.
AU - Leissring, Malcolm A.
AU - Ingelsson, Martin
AU - Matsui, Toshifumi
AU - Farris, Wesley
AU - Lu, Alice
AU - Hyman, Bradley T.
AU - Selkoe, Dennis J.
AU - Bertram, Lars
AU - Tanzi, Rudolph E.
PY - 2007/3/16
Y1 - 2007/3/16
N2 - Insulin-degrading enzyme (IDE) is a zinc metalloprotease that degrades the amyloid β-peptide, the key component of Alzheimer disease (AD)-associated senile plaques. We have previously reported evidence for genetic linkage and association of AD on chromosome 10q23-24 in the region harboring the IDE gene. Here we have presented the first functional assessment of IDE in AD families showing the strongest evidence of the genetic linkage. We have examined the catalytic activity and expression of IDE in lymphoblast samples from 12 affected and unaffected members of three chromosome 10-linked AD pedigrees in the National Institute of Mental Health AD Genetics Initiative family sample. We have shown that the catalytic activity of cytosolic IDE to degrade insulin is reduced in affected versus unaffected subjects of these families. Further, we have shown the decrease in activity is not due to reduced IDE expression, suggesting the possible defects in IDE function in these AD families. In attempts to find potential mutations in the IDE gene in these families, we have found no coding region substitutions or alterations in splicing of the canonical exons and exon 15b of IDE. We have also found that total IDE mRNA levels are not significantly different in sporadic AD versus age-matched control brains. Collectively, our data suggest that the genetic linkage of AD in this set of chromosome 10-linked AD families may be the result of systemic defects in IDE activity in the absence of altered IDE expression, further supporting a role for IDE in AD pathogenesis.
AB - Insulin-degrading enzyme (IDE) is a zinc metalloprotease that degrades the amyloid β-peptide, the key component of Alzheimer disease (AD)-associated senile plaques. We have previously reported evidence for genetic linkage and association of AD on chromosome 10q23-24 in the region harboring the IDE gene. Here we have presented the first functional assessment of IDE in AD families showing the strongest evidence of the genetic linkage. We have examined the catalytic activity and expression of IDE in lymphoblast samples from 12 affected and unaffected members of three chromosome 10-linked AD pedigrees in the National Institute of Mental Health AD Genetics Initiative family sample. We have shown that the catalytic activity of cytosolic IDE to degrade insulin is reduced in affected versus unaffected subjects of these families. Further, we have shown the decrease in activity is not due to reduced IDE expression, suggesting the possible defects in IDE function in these AD families. In attempts to find potential mutations in the IDE gene in these families, we have found no coding region substitutions or alterations in splicing of the canonical exons and exon 15b of IDE. We have also found that total IDE mRNA levels are not significantly different in sporadic AD versus age-matched control brains. Collectively, our data suggest that the genetic linkage of AD in this set of chromosome 10-linked AD families may be the result of systemic defects in IDE activity in the absence of altered IDE expression, further supporting a role for IDE in AD pathogenesis.
UR - http://www.scopus.com/inward/record.url?scp=34247244627&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34247244627&partnerID=8YFLogxK
U2 - 10.1074/jbc.M609168200
DO - 10.1074/jbc.M609168200
M3 - Article
C2 - 17244626
AN - SCOPUS:34247244627
SN - 0021-9258
VL - 282
SP - 7825
EP - 7832
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 11
ER -
