Aberrant expression of NOS isoforms in Alzheimer's disease is structurally related to nitrotyrosine formation.
Various isoforms of the nitric oxide (NO) producing enzyme nitric oxide synthase (NOS) are elevated in Alzheimer's disease (AD) indicating a critical role for NO in the pathomechanism. NO can react with superoxide to generate peroxynitrite, a process referred to as oxidative stress, which is likely to play a role in AD. Peroxynitrite in turn, nitrates tyrosine residues to form nitrotyrosine which can be identified immunohistochemically. To study the potential structural link between the increased synthesis of NO and the deposition of nitrotyrosine in AD, we analyzed the expression of neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS) in AD and control brain, and compared the localization with the distribution of nitrotyrosine. Nitrotyrosine was detected in neurons, astrocytes and blood vessels in AD cases. Aberrant expression of nNOS in cortical pyramidal cells was highly co-localized with nitrotyrosine. Furthermore, iNOS and eNOS were highly expressed in astrocytes in AD. In addition, double immunolabeling studies revealed that in these glial cells iNOS and eNOS are co-localized with nitrotyrosine. Therefore, it is suggested that increased expression of all NOS isoforms in astrocytes and neurons contributes to the synthesis of peroxynitrite which leads to generation of nitrotyrosine. In view of the wide range of isoform-specific NOS inhibitors, the determination of the most responsible isoform of NOS for the formation of peroxynitrite in AD could be of therapeutic importance in the treatment of Alzheimer's disease.
Lüth
Hans-Joachim
HJ
Paul Flechsig Institute of Brain Research, Department of Neuroanatomy, University of Leipzig, Jahnallee 59, D-04109 Leipzig, Germany. lueth@medizin.uni-leipzig.de
Münch
Gerald
G
Arendt
Thomas
T
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology*; D015415:Biomarkers; D001921:Brain / Q000166:cytology / Q000201:enzymology*; D005260:Female; D006801:Humans; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D018384:Oxidative Stress; D030421:Peroxynitrous Acid / Q000096:biosynthesis; D017966:Pyramidal Cells / Q000201:enzymology; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000096:biosynthesis*
D015415:Biomarkers; D030421:Peroxynitrous Acid; C002744:3-nitrotyrosine; D014443:Tyrosine; C496320:NOS1 protein, human; C496319:NOS2 protein, human; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III