Neuronal and glial coexpression of argininosuccinate synthetase and inducible nitric oxide synthase in Alzheimer disease

The enzyme argininosuccinate synthetase (ASS) is the rate limiting enzyme i n the metabolic pathway leading from L-citrulline to L-arginine, the physio logical substrate of all isoforms of nitric oxide synthases (NOS). ASS and inducible NOS (NOS), expression in neurons and glia. was investigated by im munohistochemistry in brains of Alzheimer disease (AD) patients and nondeme nted, age-matched controls. In 3 areas examined (hippocampus, frontal, and entorhinal cortex), a marked increase in neuronal ASS and iNOS expression w as observed in AD brains. GFAP-positive astrocytes expressing ASS were not increased in AD brains versus controls, whereas the number of iNOS expressi ng GFAP-positive astrocytes was significantly higher in AD brains. Density measurements revealed that ASS expression levels were significantly higher in glial cells of AD brains. Colocalization of ASS and iNOS immunoreactivit y was detectable in neurons and glia. Occasionally, both ASS-and NOS expres sion was detectable in CD 68-positive activated microglia cells in close pr oximity to senile plaques. These results suggest that neurons and astrocyte s express ASS in human brain constitutively, whereas neuronal and glial ASS expression increases parallel to iNOS expression in AD. Because an adequat e supply of L-arginine is indispensable for prolonged NO generation, coindu ction of ASS enables cells to sustain NO generation during AD by replenishi ng necessary supply of L-arginine.