Altered plasma arginine metabolome precedes behavioural and brain arginine metabolomic profile changes in the APPswe/PS1ΔE9 mouse model of Alzheimer's disease.

While amyloid-beta (Aß) peptides play a central role in the development of Alzheimer's disease (AD), recent evidence also implicates altered metabolism of L-arginine in the pathogenesis of AD. The present study systematically investigated how behavioural function and the brain and plasma arginine metabolic profiles changed in a chronic Aß accumulation model using male APPswe/PS1ΔE9 transgenic (Tg) mice at 7 and 13 months of age. As compared to their wild-type (WT) littermates, Tg mice displayed age-related deficits in spatial water maze tasks and alterations in brain arginine metabolism. Interestingly, the plasma arginine metabolic profile was markedly altered in 7-month Tg mice prior to major behavioural impairment. Receiver operating characteristic curve analysis revealed that plasma putrescine and spermine significantly differentiated between Tg and WT mice. These results demonstrate the parallel development of altered brain arginine metabolism and behavioural deficits in Tg mice. The altered plasma arginine metabolic profile that preceded the behavioural and brain profile changes suggests that there may be merit in an arginine-centric set of ante-mortem biomarkers for AD.

A single intracerebroventricular Aß25-35 infusion leads to prolonged alterations in arginine metabolism in the rat hippocampus and prefrontal cortex.

While amyloid beta (Aß) 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 Aß25-35 (the neurotoxic domain of the full-length Aß) 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 Aß25-35 (30 nmol/rat) or Aß35-25 (reverse peptide; 30 nmol/rat). At the 42-day time point, Aß25-35 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 Aß25-35 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 Aß25-35 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.

Agmatine protects against beta-amyloid25-35-induced memory impairments in the rat.

Amyloid beta fragment 25-35 (Abeta(25-35)) is the neurotoxic domain of the full-length Abeta(1-42) and causes memory impairments in rodents. Recent research suggests that agmatine, decarboxylated arginine, has a neuroprotective role. This study investigated the effects of a single bilateral i.c.v. infusion of aggregated Abeta(25-35) (30 nmol) in a battery of behavioural tests conducted during the period 4-6 (Experiment 1) and 4-14 (Experiment 2) weeks post-Abeta(25-35) infusion, and evaluated the protective effect of agmatine (40 mg/kg) administered i.p. 30 min prior to Abeta(25-35) infusion and once daily for a further nine consecutive days. In Experiment 1, Abeta(25-35) rats with saline treatment were not impaired in the elevated plus maze and open field and mildly impaired in the reference memory version of the water maze task, but performed poorly in the working memory version of the water maze task and the object recognition memory task, relative to the control rats that received the i.c.v. infusion of Abeta(35-25) (inactive peptide) and saline treatment. By contrast, Abeta(25-35) rats with agmatine treatment did not show performance impairments in the working memory version of the water maze task and the object recognition memory task. In Experiment 2, Abeta(25-35) rats with saline treatment were significantly impaired in the standard radial arm maze task, but only displayed no or very mild impairments in the delayed non-match to position and reference memory versions of the radial arm maze task, T-maze, object recognition memory task, both the reference and working memory versions of the water maze task, elevated plus maze and open field. By contrast, Abeta(25-35) rats with agmatine treatment were not impaired in the standard radial arm maze and performed even better than the controls in the reference memory version of the task. These results demonstrate that agmatine is able to protect against Abeta(25-35)-induced memory deficits.

Differential effects of i.c.v. microinfusion of agmatine on spatial working and reference memory in the rat.

Recent evidence suggests that agmatine, the metabolite of arginine by arginine decarboxylase, exists in the mammalian brain and is a novel neurotransmitter. Exogenous agmatine can modulate behaviour function, including learning and memory. The present study investigated the effects of repeated i.c.v. microinfusion of agmatine (once daily) on the reference and working memory versions of the water maze task, as well as the elevated plus maze and open field. Rats with high (100 microg), but not low (10 microg), dose of agmatine displayed reduced exploratory and locomotor activity in the open field relative to the saline controls on day 1 (received three infusions), but not day 12 (received 14 infusions). The three groups performed similarly on both days in the elevated plus maze tested prior to the open field. In the reference memory version of the water maze task, rats with agmatine treatment at both doses performed as well as the saline controls in the cued navigation (day 2), place navigation (days 3-7) and probe test (day 7). In the working memory version of the water maze task (days 8-11), the two agmatine groups generated markedly shorter path length and took significantly less time to reach the platform at the 180 s, but not 30 s, delay as compared to the saline group. These results demonstrate that repeated agmatine treatment produces transient impairments in exploratory and locomotor activity in the open field in a dose-dependent manner. Agmatine significantly facilitates spatial working memory at a longer delay, but not reference memory, suggesting its differential influence on the two types of spatial learning and memory. The underlying mechanisms need to be explored in the future.