Effects of chronic glucocorticoid administration on insulin-degrading enzyme and amyloid-beta peptide in the aged macaque.
Insulin-degrading enzyme (IDE) has been identified as a candidate protease in the clearance of amyloid-delta (Abeta) peptides from the brain. IDE activity and binding to insulin are known to be inhibited by glucocorticoids in vitro. In Alzheimer disease (AD), both a decrease in IDE levels and an increase in peripheral glucocorticoid levels have been documented. Our study investigated the effects of glucocorticoid treatment on IDE expression in vivo in 12 nonhuman primates (Macaca nemestrina). Year-long, high-dose exposure to the glucocorticoid cortisol (hydrocortisone acetate) was associated with reduced IDE protein levels in the inferior frontal cortex and reduced IDE mRNA levels in the dentate gyrus of the hippocampus. We assessed Abeta40 and Abeta42 levels by ELISA in the brain and in plasma, total plaque burden by immunohistochemistry, and relative Abeta1-40 and Abeta1-42 levels in the brain by mass spectrometry. Glucocorticoid treatment increased Abeta42 relative to Abeta40 levels without a change in overall plaque burden within the brain, while Abeta42 levels were decreased in plasma. These findings support the notion that glucocorticoids regulate IDE and provide a mechanism whereby increased glucocorticoid levels may contribute to AD pathology.
Kulstad
J Jacob
JJ
Geriatric Research, Education, and Clinical Center, Veteran's Affairs Puget Sound Health Care System, Seattle, Washington 98108, USA.
McMillan
Pamela J
PJ
Leverenz
James B
JB
Cook
David G
DG
Green
Pattie S
PS
Peskind
Elaine R
ER
Wilkinson
Charles W
CW
Farris
Wesley
W
Mehta
Pankaj D
PD
Craft
Suzanne
S
D000375:Aging; D016229:Amyloid beta-Peptides / Q000097:blood / Q000187:drug effects*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007339:Insulysin / Q000187:drug effects*; D008251:Macaca; D008297:Male; D010446:Peptide Fragments / Q000097:blood / Q000187:drug effects*; D012333:RNA, Messenger / Q000032:analysis / Q000187:drug effects
D016229:Amyloid beta-Peptides; D005938:Glucocorticoids; D010446:Peptide Fragments; D012333:RNA, Messenger; D007339:Insulysin