Astragaloside IV, a Natural PPARγ Agonist, Reduces Aß Production in Alzheimer's Disease Through Inhibition of BACE1.

A number of epidemiological studies have established a link between Alzheimer's disease (AD) and diabetes mellitus (DM). So, nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) plays an important role in the treatment of AD. However, current PPARγ-targeting drugs such as thiazolidinediones (TZDs) are associated with undesirable side effects. We identified herbal extract with a small molecular, astragaloside IV (AS-IV), as a selective PPARγ natural agonist in nervous cells by developing a PPAR-PPRE pathway regulatory system. Cultured SH-SY5Y cells transfected with pEGFP-N1-BACE1 were treated with AS-IV for 24 h or AS-IV plus the PPAR-γ antagonist GW9662 in vitro. APP/PS1 mice were intragastrically treated with AS-IV or AS-IV plus the GW9662 every 48 h for 3 months. Immunofluorescence, western blotting, and real-time PCR were used to examine the expression of PPARγ and BACE1. Immunohistochemical staining was performed to analyze the distribution of Aß plaques in the APP/PS1 mouse brain. The levels of Aß were determined using ELISA kits. AS-IV was shown to be a PPARγ agonist by establishing a high-throughput screening model for PPARγ agonists. The results showed that AS-IV treatment increased activity of PPARγ and inhibited BACE1 in vitro. As a result, Aß levels decreased significantly. GW9662, which is a PPARγ antagonist, significantly blocked the beneficial role of AS-IV. In vivo, AS-IV treatment increased PPARγ and BACE1 expression and reduced neuritic plaque formation and Aß levels in the brains of APP/PS1 mice. These effects of AS-IV could be effectively inhibited by GW9662. These results indicate that AS-IV may be a natural PPARγ agonist that suppressed activity of BACE1 and ultimately attenuates generation of Aß. Therefore, AS-IV may be a promising agent for modulating Aß-related pathology in AD.

Streptozotocin-induced diabetes increases amyloid plaque deposition in AD transgenic mice through modulating AGEs/RAGE/NF-κB pathway.

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.

KFe2Se2 is the parent compound of K-doped iron selenide superconductors.

We elucidate the existing controversies in the newly discovered K-doped iron selenide (K(x)Fe(2-y)Se(2-z)) superconductors. The stoichiometric KFe(2)Se(2) with √2 × âˆš2 charge ordering was identified as the parent compound of K(x)Fe(2-y)Se(2-z) superconductor using scanning tunneling microscopy and spectroscopy. The superconductivity is induced in KFe(2)Se(2) by either Se vacancies or interacting with the antiferromagnetic K(2)Fe(4)Se(5) compound. In total, four phases were found to exist in K(x)Fe(2-y)Se(2-z): parent compound KFe(2)Se(2), superconducting KFe(2)Se(2) with √2 × âˆš5 charge ordering, superconducting KFe(2)Se(2-z) with Se vacancies, and insulating K(2)Fe(4)Se(5) with √5 × âˆš5 Fe vacancy order. The phase separation takes place at the mesoscopic scale under standard molecular beam epitaxy conditions.

Valproate reduces tau phosphorylation via cyclin-dependent kinase 5 and glycogen synthase kinase 3 signaling pathways.

Valproate (VPA) is a widely used anticonvulsant and mood-stabilizing drug. Recent studies have shown that VPA could reduce amyloid-ß 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 12 weeks), 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 3ß (GSK3ß), 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 GSK3ß. Our present data suggest that the inhibitory effects of VPA on tau hyperphosphorylation might be mediated through both CDK5 and GSK3ß signaling pathways.