AGMATINE RESCUES SPATIAL LEARNING AND MEMORY AND SUPPRESSES POLYAMINE STRESS RESPONSE IN PS19 TAU MICE

Tauopathies are characterised by the accumulation of the hyperphosphorylated microtubule-associated protein tau (MAPT) in the brain. PS19 mice bearing the MAPT P30LS mutation recapitulate tau pathology and behavioural changes of tauopathies, and display altered polyamine metabolism in the brain with a sustained polyamine stress response. Agmatine has anti-inflammatory, neuroprotective and memory-enhancing properties and plays a critical role in regulating polyamine production. This study therefore assessed the effects of agmatine supplementation (50 mg/kg daily via food chow) on behavioural functions and brain polyamine profile in PS19 mice from 2 months of age for a duration of 3 months. Consistent with previous literature, PS19 mice displayed spatial learning and working memory deficits and increased polyamine levels (putrescine and spermidine in particular) relative to wildtype controls. Intriguingly, agmatine supplementation to PS19 mice attenuated working memory deficits in the Y-maze and restored spatial working memory in the water maze. Moreover, agmatine supplementation markedly reduced the brain tissue content of polyamine putrescine and spermidine in PS19 mice, although had no effects on mRNA expression of enzymes involved in polyamine biosynthesis and retro-conversion. This study, for the first time, demonstrated that oral agmatine supplementation rescued spatial learning and memory and suppressed the polyamine stress response in PS19 mice. These findings merit future research to explore the preventive and therapeutic potential of agmatine for tauopathies by targeting polyamines.