Pre-aggregated Aβ(25-35) alters arginine metabolism in the rat hippocampus and prefrontal cortex.

Amyloid beta (Aβ) has been proposed to play a central and causative role in the development of Alzheimer's disease. Aβ(25-35), the neurotoxic domain of the full-length Aβ, causes learning and memory impairments in rodents. The present study investigated the effects of a single bilateral i.c.v. infusion of pre-aggregated Aβ(25-35) (30 nmol/rat) on animals' performance in the open field, and on arginine metabolic enzymes and metabolites in the CA1, CA2/3, and dentate gyrus (DG) sub-regions of the hippocampus and prefrontal cortex (PFC) at the time point of 6-8 days after Aβ infusion. Aβ(25-35) rats displayed reduced exploratory activity in the open field relative to the Aβ(35-25) (reverse peptide; 30 nmol) rats. Aβ(25-35) resulted in significantly decreased nitric oxide synthase (NOS) activity and endothelial NOS protein expression, but increased arginase activity, arginase II protein expression, and ornithine and putrescine levels, in hippocampal CA2/3. There were increased glutamate and putrescine levels in the DG, but decreased agmatine levels in the DG and PFC, in the Aβ(25-35) group relative to the Aβ(35-25) one. Cluster analyses were performed to determine if the nine related neurochemical variables (arginine, citrulline, ornithine, agmatine, putrescine, spermidine, spemine, glutamate, and GABA) formed distinct groups, and whether it changed as a function of Aβ(25-35). There were substantially different clusters between the two groups in the hippocampus and PFC. These results demonstrate that Aβ(25-35) alters arginine metabolism, which further supports the prominent role of arginine and its metabolites in Alzheimer's disease (AD) pathogenesis.