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Hypoxia was shown to be associated with an increased risk of Alzheimer's disease (AD). The effects of hypoxia on the development of AD pathology and spatial memory ability and the possible molecular mechanisms remain poorly understood. In this study, we demonstrate that rats exposed to a hypoxic condition (10% oxygen concentration) for 1, 2, 4 and 8 weeks (6 h each day) displayed spatial memory impairment and increased tau phosphorylation at Ser198/199/202, Thr205, Ser262, Ser396 and Ser404 in the hippocampus. Concomitantly, the levels of Tyr216-phosphorylated glycogen synthase kinase (GSK)-3β (activated form of GSK-3β) and Tyr307-phosphorylated protein phosphatase 2A (inactivated form of PP2A) were significantly increased in the hippocampus of the rats with 1, 2, 4 and 8 weeks of hypoxia exposure, while the levels of methylated PP2A (activated form of PP2A) were significantly decreased in the hippocampus of the rats with 4 and 8 weeks of hypoxia exposure. In addition, the content of malondialdehyde, an indicator of oxidative stress, was elevated, whereas the activity of superoxide dismutase was not significantly changed in the hippocampus of the rats exposed to hypoxia. Taken together, these data demonstrated that hypoxia induced tau hyperphosphorylation and memory impairment in rats, and that the increased tau phosphorylation could be attributed to activation of GSK-3β and inactivation of PP2A. These data suggest that interventions to improve hypoxia may be helpful to prevent the development of AD pathology and cognitive impairment., (© 2014 S. Karger AG, Basel.)

Hyperhomocysteinemia is associated with an increased risk of Alzheimer's disease (AD). Our previous work has demonstrated that combined folate and vitamin B12 (vit-B12) supplementation prevents tau hyperphosphorylation and memory deficits induced by acute administration of homocysteine in young rats. Here, we further investigated whether folate/vit-B12 supplementation is also effective in aged rats with a chronically high level of homocysteine. 18-month-old rats were injected with homocysteine via the vena caudalis with or without a concurrent folate/vit-B12 supplementation for 28 weeks. We found that hyperhomocysteinemia induced tau hyperphosphorylation and accumulation in hippocampus and cortex. Concurrent signaling changes included the activation of glycogen synthase kinases-3β, cyclin-dependent kinase-5, c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38MAPK, and inhibition of protein phosphatase 2A. Although the ability to learn was not affected, the aged rats exhibited significant memory deficits. Folate/vit-B12 supplementation attenuated these biochemical and behavioral correlates. These data demonstrate that folate/vit-B12 supplementation is also effective in a chronic hyperhomocysteinemia model in reversing the AD-like tau pathologies and memory deficits.

Tau hyperphosphorylation and memory deficit are characteristic alterations of Alzheimer's disease (AD), and glycogen synthase kinase-3 (GSK-3) plays a crucial role in these AD-like changes. We have reported that activation of GSK-3 through ventricular injection of wortmannin and GF-109203X (WT/GFX, 100 microM each) induces tau hyperphosphorylation and memory impairment of rats [Liu, S.J. et al., 2003. Overactivation of glycogen synthase kinase-3 by inhibition of phosphoinositol-3 kinase and protein kinase C leads to hyperphosphorylation of tau and impairment of spatial memory. J. Neurochem. 87, 1333-1344]. By using this model, we explored in the present study the effects of dehydroevodiamine (DHED), a quinazoline alkaloid isolated from Evodia rutaecarpa Bentham, on the memory retention, tau phosphorylation and the activity of GSK-3. We found that pre-administration of DHED through vena caudalis for 1 week efficiently improved the WT/GFX-induced spatial memory retention impairment of the rats; it also antagonized tau hyperphosphorylation at multiple AD sites and arrested the overactivation of GSK-3 induced by WT/GFX. Our study gave the first in vivo evidence that DHED could suppress the overactivation of GSK-3 and improve tau hyperphosphorylation and spatial memory deficit of the rats, suggesting that this chemical may be served as a candidate for arresting AD-like pathological and behavioral alterations.

Objectives: Arctigenin (ATG) is a natural product with a variety of biological activity, which can improve the pathological changes of Alzheimer's disease (AD) model mice through multiple mechanisms. This study aims to further elucidate the potential mechanism by which ATG improves memory impairment in AD mice. Methods: Here, we used pR5 mice as an experimental model, and ATG was administered continuously for 90 days. Novel object recognition, Y-maze, and Morris water maze were used to evaluate the therapeutic effect of ATG on memory impairment in AD mice. Immunohistochemical and immunofluorescence analyses were used to evaluate the effects of ATG on tau hyperphosphorylation and neuroinflammation, respectively. Finally, proteomics techniques were used to explore the possible mechanism of ATG. Key findings: ATG significantly improved memory impairment in pR5 mice and inhibited tau phosphorylation in the hippocampus and neuroinflammation in the cortex. According to the proteomic analysis, the altered cognitive function of ATG was associated with the proteins of the tricarboxylic acid cycle and the electron transport chain. Conclusion: These results suggest that ATG is a potential therapeutic agent for diseases related to aberrant energy metabolism that can treat AD by improving mitochondrial function. [ABSTRACT FROM AUTHOR]

Hyperbilirubinemia may increase the risk of Alzheimer's disease (AD) but its mechanistic role in AD pathogenesis remains obscure. Here, we used animal models to investigate the short- and long-term effects of neonatal systemic exposure to bilirubin on brain histology and function as well as the acute effect of lateral ventricle injection of bilirubin in adult rats. We found that three days exposure to bilirubin in newborn rats could induce AD-like pathological changes in late life, including tau protein hyperphosphorylation at multiple sites, increased Aβ production in brain tissues, and spatial learning and memory injury. Bilirubin activated the activities of several protein kinases (GSK-3β, CDK5, and JNK), which were positively correlated with hyperphosphorylated tau; simultaneously increased the expression of AβPP γ-secretase PS2 and decreased the expression of α-secretase ADAM17, which were positively correlated with Aβ production. The above results were well replicated in primary hippocampal cell cultures. These data demonstrate that bilirubin encephalopathy is an AD-like disease, suggesting a potent role of bilirubin in AD. [ABSTRACT FROM AUTHOR]