Protein disulfide isomerase in Alzheimer disease.
There is a great deal of evidence that places oxidative stress as a proximal event in the natural history of Alzheimer disease (AD). In addition to increased damage, there are compensatory increases in the levels of free sulfhydryls, glucose-6-phosphate dehydrogenase, and NAD(P)H:quinone oxidoreductase 1. To investigate redox homeostasis further in AD, we analyzed protein disulfide isomerase (PDI), a multifunctional enzyme, which catalyzes the disruption and formation of disulfide bonds. PDI plays a pivotal role in both secreted and cell-surface-associated protein disulfide rearrangement. In this study, we show that PDI specifically localizes to neurons, where there is no substantial increase in AD compared to age-matched controls. These findings indicate that the neurons at risk of death in AD do not show a substantial change in PDI to compensate for the increased sulfhydryls and reductive state found during the disease. This suggests that, despite compensatory reductive changes in AD, the level of PDI is sufficiently high physiologically in neurons to accommodate a more reducing environment.
Kim
H T
HT
Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
Russell
R L
RL
Raina
A K
AK
Harris
P L
PL
Siedlak
S L
SL
Zhu
X
X
Petersen
R B
RB
Shimohama
S
S
Smith
M A
MA
Perry
G
G
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology*; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001344:Autopsy; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003720:Densitometry; D004220:Disulfides; D006624:Hippocampus / Q000201:enzymology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008875:Middle Aged; D009474:Neurons / Q000201:enzymology; D018384:Oxidative Stress; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D004220:Disulfides; D019704:Protein Disulfide-Isomerases