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4 Allele
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From the Geriatric Research, Education, and Clinical Center,* and the Mental Illness Research, Education, and Clinical Center, Veteran Affairs Puget Sound Health Care System, Seattle, Washington; the Departments of Psychiatry and Behavioral Sciences,¶ Medicine, Pharmacology, Neurology,|| Pathology, and Psychology,** University of Washington School of Medicine, Seattle, Washington; and the Department of Molecular Pharmacology, Stanford University Medical School, Stanford, California
Aß is the major component of amyloid plaques characterizing Alzheimer’s disease (AD). Aß 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 Aß 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 
4+ AD patients compared to 4- patients and controls. The allele-specific decrease of IDE in 4+ 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 4 allele compared to AD and normal subjects without the 4 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 Aß metabolism.
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