A single intracerebroventricular Aβ25–35 infusion leads to prolonged alterations in arginine metabolism in the rat hippocampus and prefrontal cortex

Abstract

While amyloid beta (Aβ) plays a central role in the development of Alzheimer’s disease (AD), recent evidence suggests the involvement of arginine metabolism in AD pathogenesis. Earlier research has shown that a single intracerebroventricular (i.c.v.) infusion of pre-aggregated Aβ25–35 (the neurotoxic domain of the full-length Aβ) altered arginine metabolism in the rat hippocampus (particularly the CA2/3 and dentate gyrus (DG) sub-regions) and prefrontal cortex (PFC) at the time point of 8days post-infusion. The present study measured the levels of l-arginine and its nine downstream metabolites (l-citrulline, l-ornithine, agmatine, putrescine, spermidine, spermine, glutamate, GABA and glutamine) in the hippocampus and PFC at the time points of 42 and 97days following a single bilateral i.c.v. infusion of Aβ25–35 (30nmol/rat) or Aβ35–25 (reverse peptide; 30nmol/rat). At the 42-day time point, Aβ25–35 resulted in decreased levels of glutamate, glutamine and spermine in the CA2/3 sub-region of the hippocampus. At the 97-day time point, however, there were decreased l-ornithine, GABA and putrescine levels, but increased glutamate/GABA ratio, in the PFC and increased spermine levels in the DG sub-region. Cluster analyses showed that l-arginine and its three main metabolites l-citrulline, l-ornithine and agmatine formed distinct groups, which changed as a function of Aβ25–35 at the 42-day and 97-day time points, particularly in the CA2/3 and PFC regions respectively. This study, for the first time, demonstrates that a single i.c.v. infusion of pre-aggregated Aβ25–35 leads to prolonged alterations in arginine metabolism in a region-specific and time-dependent manner, which further supports the involvement of arginine metabolism in AD pathogenesis.