Aberrant expression of myeloperoxidase in astrocytes promotes phospholipid oxidation and memory deficits in a mouse model of Alzheimer disease.
Myeloperoxidase (MPO) is expressed in Alzheimer disease (AD) but not normal aged brain. A functional -463G/A MPO promoter polymorphism has been associated with AD risk through as yet unidentified mechanisms. Here we report that human MPO-463G allele, but not MPO-463A or mouse MPO, is strongly expressed in astrocytes and deposited in plaques in huMPO transgenic mice crossed to the APP23 model. MPO is similarly expressed in astrocytes in human AD tissue. In cortical homogenates of the MPOG-APP23 model, MPO expression correlated with increased levels of a lipid peroxidation product, 4-hydroxynonenal. Fluorescence high-performance liquid chromatography and electrospray ionization mass spectroscopy identified selective accumulation of phospholipid hydroperoxides in two classes of anionic phospholipids, phosphatidylserine (PS-OOH) and phosphatidylinositol (PI-OOH). The same molecular species of PS-OOH and PI-OOH were elevated in human AD brains as compared with non-demented controls. Augmented lipid peroxidation in MPOG-APP23 mice correlated with greater memory deficits. We suggest that aberrant huMPO expression in astrocytes leads to a specific pattern of phospholipid peroxidation and neuronal dysfunction contributing to AD.
Maki
Richard A
RA
Sidney Kimmel Cancer Center, San Diego, California 92121.
Tyurin
Vladimir A
VA
Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219.
Lyon
Robert C
RC
Sidney Kimmel Cancer Center, San Diego, California 92121.
Hamilton
Ronald L
RL
Departments of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219.
DeKosky
Steven T
ST
Departments of Pathology and Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania 15219.
Kagan
Valerian E
VE
Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219.
Reynolds
Wanda F
WF
Sidney Kimmel Cancer Center, San Diego, California 92121. Electronic address: wreynolds@skcc.org.
D000483:Alleles; D000544:Alzheimer Disease / Q000201:enzymology*; D000818:Animals; D001253:Astrocytes / Q000201:enzymology*; D001921:Brain / Q000201:enzymology; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D015227:Lipid Peroxidation; D008569:Memory Disorders / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009195:Peroxidase / Q000235:genetics / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism*; D013050:Spectrometry, Fluorescence; D021241:Spectrometry, Mass, Electrospray Ionization
D010743:Phospholipids; D009195:Peroxidase