title: 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 8 days 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 97 days following a single bilateral i.c.v. infusion of Aβ25-35 (30 nmol/rat) or Aβ35-25 (reverse peptide; 30 nmol/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.
authors.affiliation: Department of Anatomy, University of Otago, Dunedin, New Zealand; School of Pharmacy, University of Otago, Dunedin, New Zealand; Brain Health Research Centre, University of Otago, Dunedin, New Zealand.
authors.forename: D H
authors.initials: DH
authors.lastname: Bergin
authors.affiliation: Department of Anatomy, University of Otago, Dunedin, New Zealand; Brain Health Research Centre, University of Otago, Dunedin, New Zealand.
authors.forename: Y
authors.initials: Y
authors.lastname: Jing
authors.affiliation: Department of Anatomy, University of Otago, Dunedin, New Zealand; School of Pharmacy, University of Otago, Dunedin, New Zealand; Brain Health Research Centre, University of Otago, Dunedin, New Zealand.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Anatomy, University of Otago, Dunedin, New Zealand; Brain Health Research Centre, University of Otago, Dunedin, New Zealand. Electronic address: ping.liu@otago.ac.nz.
authors.forename: P
authors.initials: P
authors.lastname: Liu
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000378:metabolism*; D016000:Cluster Analysis; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D057967:Infusions, Intraventricular; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology*; D011073:Polyamines / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000596:Amino Acids; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D011073:Polyamines; C074636:amyloid beta-protein (25-35); D001120:Arginine
keywords: amyloid beta; arginine metabolism; glutamate; hippocampus; polyamines; prefrontal cortex