Apolipoprotein E isoform mediated regulation of nitric oxide release.
Progressive dysfunction and death of neurons in Alzheimer's dementia is enhanced in patients carrying one or more APOE4 alleles who also display increased presence of oxidative stress markers. Modulation of oxidative stress is a nontraditional and physiologically relevant immunomodulatory function of apolipoprotein E (apoE). Stimulated peritoneal macrophages from APOE-transgenic replacement (APOE-TR) mice expressing only human apoE3 or human apoE4 protein isoforms were utilized as mouse models to investigate the role of apoE protein isoforms and gender in the regulation of oxidative stress. Macrophages from male APOE4/4-TR mice produced significantly higher levels of nitric oxide than from male APOE3/3-TR mice, while macrophages from female APOE3/3-TR and female APOE4/4-TR mice produced the similar levels of nitric oxide. Primary cultures of microglial cells of APOE4 transgenic mice also produced significantly more nitric oxide than microglia from APOE3 transgenic mice. These data suggest a potentially novel mechanism for gender-dependent and apoE isoform-dependent immune responses that parallel the genetic susceptibility of APOE4 carriers for the development of Alzheimer's disease.
Brown
Candice M
CM
University Program in Genetics, Department of Medicine (Neurology), Duke University Medical Center, Durham, NC 27710, USA.
Wright
Elizabeth
E
Colton
Carol A
CA
Sullivan
Patrick M
PM
Laskowitz
Daniel T
DT
Vitek
Michael P
MP
D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism*; D000818:Animals; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000378:metabolism*; D003433:Crosses, Genetic; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism; D010537:Peritoneum / Q000378:metabolism; D020033:Protein Isoforms
D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D009573:Nitrites; D020033:Protein Isoforms; D009569:Nitric Oxide