P2‐332: Melatonin attenuates Aβ amyloidosis and induces tau hyperphosphorylation in transgenic mice Tg2576 of different ages

Key pathological hallmarks of Alzheimer's disease (AD) are the deposition of amyloid plaques containing Aβ-peptides and the formation of neurofibrillary tangles containing hyperphosphorylated tau. APPsw transgenic mice (Tg2576) overproducing mutant amyloid β protein precursor (βAPP) show substantial brain Aβ amyloidosis and behavioural abnormalities. In Tg2576, Aβ deposits induce phosphorylated tau accumulated at 8-10 months. Phosphorylated tau at Ser199, Thr231/Ser235, Thr205 and Ser404 accumulated in different ages. The major kinase for tau phosphorylation was GSK3β and CDK-5. The pineal and retinal melatonin regulates endogenous circadian rhythms, and has various physiological functions including neuromodulatory and vasoactive actions, antioxidative and neuroprotective properties. Our recent studies have demonstrated that melatonin efficiently attenuates Alzheimer-like tau hyperphosphorylation in Tg2576. Four-month-old (n = 4-5)and Eight-month-old (n = 4-5) Tg2576 animals (Tgs) were daily injections of melatonin (14mg/kg) for 4 months. Respective controls included non-transgenic littermates (Lts) (n = 4-5), and untreated Tgs (n = 4-5). After 4 months of treatment, Hyperphosphorylated tau, GSK-3β and CDK5 were determined by Western blotting, immunohistochemistry with specific antibodies. The long-term influence of melatonin on behavior, biochemical and neuropathologic changes in Tg2576. In Eight-month-old mice, Hyperphosphorylated tau epitopes were substantially decreased as assessed with the pT205 and pS404 antibodies in mel-treated Tg mice. The untreated Tg mice show increased levels of tau hyperphosphorylation and increased activated CDK5. In twelve-month-old mice, Hyperphosphorylated tau were substantially decreased as assessed with the pT231 antibodies in mel-treated Tg mice. The untreated Tg mice show, together with increased amyloidogenesis, increased levels of tau hyperphosphorylation and increased activated GSK-3β. Four months of Melatonin treatment reduced the burden of amyloid plaques and the levels of hyperphosphorylated tau. Melatonin reduced the activated CDK5 and GSK-3β respectivly in 8 months and 12 months. Melatonin can exert multiple protective effects on both amyloidogenesis and tau hyperphosphorylation via regulate the activated CDK5 and GSK-3β in transgenic mice Tg2576 of different ages.