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Background: An increasing number of studies have demonstrated of that diabetes mellitus (DM) is associated with an increased prevalence of Alzheimer disease (AD), the underlying mechanisms are still obscure. Methods: We developed a streptozotocin (STZ)-induced diabetic AD transgenic mouse model and evaluated the effect of hyperglycemia on senile plaque formation. Results: Our data showed that administration of STZ increased the level of blood glucose and increased the advanced glycation end products (AGEs) in brain tissue, and further enhanced the expression levels of the receptor for AGEs (RAGE) and the nuclear factor-kappa B (NF-κB) in the brain, and accelerated the senile plaque formation in the transgenic mice. Our results showed that STZ-induced insulin-deficient hyperglycemia caused the pathophysiology of AD in APP/PS1 transgenic mice by modulating the AGEs/RAGE/NF-κB pathway. Conclusions: Our study suggests that there is a close linkage of DM and cerebral amyloidosis in the pathogenesis of AD. [ABSTRACT FROM AUTHOR]

Abstract: Valproate (VPA) is a widely used anticonvulsant and mood-stabilizing drug. Recent studies have shown that VPA could reduce amyloid-β generation, and improve memory deficits in transgenic mouse models of Alzheimer''s disease (AD). However, whether VPA affects tau phosphorylation and the underlying mechanism has not been established. Here, we showed that systemic treatment of APP and presenilin 1 double transgenic mice with VPA (50mg/kg, once a day for 12weeks), significantly reduced the levels of tau phosphorylation at the sites of Thr205, Ser396 and Thr231. Meanwhile, VPA treatment markedly reduced the activities of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK3β), two protein kinases involved in abnormal hyperphosphorylation of tau. In an okadaic acid-induced tau hyperphosphorylation SH-SY5Y cell model, the anti-tau-phosphorylation effect of VPA was further confirmed, accompanied by a marked decrease in the activities of CDK5 and GSK3β. Our present data suggest that the inhibitory effects of VPA on tau hyperphosphorylation might be mediated through both CDK5 and GSK3β signaling pathways. [Copyright &y& Elsevier]

[Display omitted] • Melatonin and trientine were formed into a new compound melatonin-trientine (TM). • TM combines the functions both of antioxidant effects and chelate excessive metal ions. • TM decreases Aβ deposition in the brains of the APP/PS1 mice. • TM promotes APP non-amyloidogenic processing. • TM blocks tau hyperphosphorylation, neuronal degeneration, neuroinflammation, and oxidative stress. Researchers continue to explore drug targets to treat the characteristic pathologies of Alzheimer's disease (AD). Some drugs relieve the pathological processes of AD to some extent, but the failed clinical trials indicate that multifunctional agents seem more likely to achieve the therapy goals for this neurodegenerative disease. Herein, a novel compound named melatonin-trientine (TM) has been covalently synthesized with the natural antioxidant compounds melatonin and the metal ion chelator trientine. After toxicological and pharmacokinetic verification, we elucidated the effects of intraperitoneal administration of TM on AD-like pathology in 6-month-old mice that express both the β-amyloid (Aβ) precursor protein and presenilin-1 (APP/PS1). We found that TM significantly decreased Aβ deposition and neuronal degeneration in the brains of the APP/PS1 double transgenic mice. This result may be due to the upregulation of iron regulatory protein-2 (IRP2), insulin degrading enzyme (IDE), and low density lipoprotein receptor related protein 1 (LRP1), which leads to decreases in APP and Aβ levels. Additionally, TM may promote APP non-amyloidogenic processing by activating the melatonin receptor-2 (MT2)-dependent signaling pathways, but not MT1. In addition, TM plays an important role in blocking γ-secretase, tau hyperphosphorylation, neuroinflammation, oxidative stress, and metal ion dyshomeostasis. Our results suggest that TM may effectively maximize the therapeutic efficacy of targeting multiple mechanisms associated with AD pathology. [ABSTRACT FROM AUTHOR]