title: Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-epsilon4 allele.
abstract: Abeta is the major component of amyloid plaques characterizing Alzheimer's disease (AD). Abeta accumulation can be affected by numerous factors including increased rates of production and/or impaired clearance. Insulin-degrading enzyme (IDE) has been implicated as a candidate enzyme responsible for the degradation and clearance of Abeta in the brain. We have previously shown that AD patients exhibit abnormalities in insulin metabolism that are associated with apoliprotein E (APOE) status. The possible association of IDE with AD, as well as the link between APOE status and insulin metabolism, led us to examine the expression of IDE in AD. We report that hippocampal IDE protein is reduced by approximately 50% in epsilon4+ AD patients compared to epsilon4- patients and controls. The allele-specific decrease of IDE in epsilon4+ AD patients is not associated with neuronal loss since neuron-specific enolase levels were comparable between the AD groups, regardless of APOE status. Hippocampal IDE mRNA levels were also reduced in AD patients with the epsilon4 allele compared to AD and normal subjects without the epsilon4 allele. These findings show that reduced IDE expression is associated with a significant risk factor for AD and suggest that IDE may interact with APOE status to affect Abeta metabolism.
authors.affiliation: Geriatric Research, Education, and Clinical Center, Veteran Affairs Puget Sound Health Care System, Seattle, Washington 98108, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Cook
authors.forename: James B
authors.initials: JB
authors.lastname: Leverenz
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: McMillan
authors.forename: J Jacob
authors.initials: JJ
authors.lastname: Kulstad
authors.forename: Sasha
authors.initials: S
authors.lastname: Ericksen
authors.forename: Richard A
authors.initials: RA
authors.lastname: Roth
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
authors.forename: Lee-Way
authors.initials: LW
authors.lastname: Jin
authors.forename: Kristina S
authors.initials: KS
authors.lastname: Kovacina
authors.forename: Suzanne
authors.initials: S
authors.lastname: Craft
mesh_terms: D000368:Aged; D000483:Alleles; D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics*; D015153:Blotting, Western; D005260:Female; D006624:Hippocampus / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007339:Insulysin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D012333:RNA, Messenger; D007339:Insulysin