Altered Arginine Metabolism in Cells Transfected with Human Wild-Type Beta Amyloid Precursor Protein (?APP)

E-ISSN： 1875-5828|13|9|1030-1039

ISSN： 1567-2050

Source： Current Alzheimer Research, Vol.13, Iss.9, 2016-07, pp. : 1030-1039

Disclaimer: Any content in publications that violate the sovereignty, the constitution or regulations of the PRC is not accepted or approved by CNPIEC.

Previous Menu Next

Abstract

Alterations of enzymes linked to arginine metabolism have been recently implicated inAlzheimer's disease (AD). Despite strong association of arginine changes with nitric oxide (NO)pathway, the impact of amyloid ? (A?) peptides on arginine degradation and re-synthesis is unknown.In the present study we compared expression levels of arginases (ARG1, ARG2), neuronal, endothelialand inducible NO synthase isoforms (NNOS, ENOS, INOS), enzymes that metabolize arginine or resynthesizeit from citrulline and the levels of corresponding amino acids in rat pheochromocytoma (PC12) cells overexpressinghuman A? precursor protein (APPwt cells). Moreover, we investigated the changes in miRNAs responsible formodulation of arginine metabolism in AD brains. Real-time PCR analysis revealed in APPwt cells significant decreases ofARG1 and ARG2 which are responsible for lysing arginine into ornithine and urea; this reduction was followed by significantlylower enzyme activity. NNOS and ENOS mRNAs were elevated in APPwt cells while iNOS was undetectable inboth cell lines. The expression of argininosuccinate synthase (ASS) that metabolizes citrulline was down-regulated withoutchanges in argininosuccinate lyase (ASL). Ornithine decarboxylase (ODC), which decarboxylates ornithine to form putrescinewas also reduced. Arginine, the substrate for both arginases and NOS, was unchanged in APPwt cells. However,citrulline concentration was significantly higher. Elevated miRNA-9 and miRNA-128a found in AD brain tissues mightmodulate the expression of ASS and NOS, respectively. Our results indicate that A? affects arginine metabolism and thisinfluence might have important role in the pathomechanism of AD.