Alterations of enzymes linked to arginine metabolism have been recently implicated in
Alzheimer's disease (AD). Despite strong association of arginine changes with nitric oxide (NO)
pathway, the impact of amyloid β (Aβ) peptides on arginine degradation and re-synthesis is unknown.
In the present study we compared expression levels of arginases (ARG1, ARG2), neuronal, endothelial
and inducible NO synthase isoforms (NNOS, ENOS, INOS), enzymes that metabolize arginine or resynthesize
it from citrulline and the levels of corresponding amino acids in rat pheochromocytoma (PC12) cells overexpressing
human Aβ precursor protein (APPwt cells). Moreover, we investigated the changes in miRNAs responsible for
modulation of arginine metabolism in AD brains. Real-time PCR analysis revealed in APPwt cells significant decreases of
ARG1 and ARG2 which are responsible for lysing arginine into ornithine and urea; this reduction was followed by significantly
lower enzyme activity. NNOS and ENOS mRNAs were elevated in APPwt cells while iNOS was undetectable in
both cell lines. The expression of argininosuccinate synthase (ASS) that metabolizes citrulline was down-regulated without
changes in argininosuccinate lyase (ASL). Ornithine decarboxylase (ODC), which decarboxylates ornithine to form putrescine
was 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 might
modulate the expression of ASS and NOS, respectively. Our results indicate that Aβ affects arginine metabolism and this
influence might have important role in the pathomechanism of AD.