APOE genotype-specific differences in human and mouse macrophage nitric oxide production.
Individuals expressing an APOE4 genotype demonstrate increased Alzheimer's disease (AD) neuropathology and a decreased onset age. The APOE4 gene may act by modulating the CNS immune response. Using human monocyte-derived macrophages (MDM), we show a significantly greater increase in NO production during immune activation in MDM from APOE4 AD patients compared to normal, age-matched individuals or to AD patients with an APOE 3/3 genotype. Microglia and peritoneal macrophages from APOE4 targeted replacement mice demonstrate a similar increase in NO compared to the APOE3 targeted replacement mice. The enhanced macrophage responsiveness and the increased production of NO in APOE4 AD patients may predispose the CNS to an increased potential for nitration and nitrosation, consistent with the redox imbalance and neuroinflammatory state seen in AD.
Colton
Carol A
CA
Division of Neurology and the Alzheimer's Disease Research Center, Duke University Medical Center, Durham, NC 27710, USA. glia01@aol.com
Needham
Leila K
LK
Brown
Candice
C
Cook
Danielle
D
Rasheed
Karima
K
Burke
James R
JR
Strittmatter
Warren J
WJ
Schmechel
Donald E
DE
Vitek
Michael P
MP
D000368:Aged; D000544:Alzheimer Disease / Q000097:blood / Q000150:complications / Q000235:genetics; D000818:Animals; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics*; D016022:Case-Control Studies; D002478:Cells, Cultured; D003704:Dementia / Q000097:blood / Q000150:complications / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000201:enzymology; D008875:Middle Aged; D009000:Monocytes / Q000201:enzymology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013045:Species Specificity
D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D012333:RNA, Messenger; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse