Decreased catalytic activity of the insulin-degrading enzyme in chromosome 10-linked Alzheimer disease families.
Insulin-degrading enzyme (IDE) is a zinc metalloprotease that degrades the amyloid beta-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.
Kim
Minji
M
Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts 02129, and Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington 40536, USA.
Hersh
Louis B
LB
Leissring
Malcolm A
MA
Ingelsson
Martin
M
Matsui
Toshifumi
T
Farris
Wesley
W
Lu
Alice
A
Hyman
Bradley T
BT
Selkoe
Dennis J
DJ
Bertram
Lars
L
Tanzi
Rudolph E
RE
D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism; D002384:Catalysis; D002879:Chromosomes, Human, Pair 10 / Q000648:ultrastructure*; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007339:Insulysin / Q000235:genetics* / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree
D007328:Insulin; D007339:Insulysin