ABSTRACT
Activation of liver X receptors (LXRs) by synthetic agonists was found to improve cognition in Alzheimer's disease (AD) mice. However, these LXR agonists induce hypertriglyceridemia and hepatic steatosis, hampering their use in the clinic. We hypothesized that phytosterols as LXR agonists enhance cognition in AD without affecting plasma and hepatic triglycerides. Phytosterols previously reported to activate LXRs were tested in a luciferase-based LXR reporter assay. Using this assay, we found that phytosterols commonly present in a Western type diet in physiological concentrations do not activate LXRs. However, a lipid extract of the 24(S)-Saringosterol-containing seaweed Sargassum fusiforme did potently activate LXRß. Dietary supplementation of crude Sargassum fusiforme or a Sargassum fusiforme-derived lipid extract to AD mice significantly improved short-term memory and reduced hippocampal Aß plaque load by 81%. Notably, none of the side effects typically induced by full synthetic LXR agonists were observed. In contrast, administration of the synthetic LXRα activator, AZ876, did not improve cognition and resulted in the accumulation of lipid droplets in the liver. Administration of Sargassum fusiforme-derived 24(S)-Saringosterol to cultured neurons reduced the secretion of Aß42. Moreover, conditioned medium from 24(S)-Saringosterol-treated astrocytes added to microglia increased phagocytosis of Aß. Our data show that Sargassum fusiforme improves cognition and alleviates AD pathology. This may be explained at least partly by 24(S)-Saringosterol-mediated LXRß activation.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid beta-Peptides/genetics , Liver X Receptors/genetics , Neuroprotective Agents/pharmacology , Peptide Fragments/genetics , Plaque, Amyloid/drug therapy , Sargassum/chemistry , Stigmasterol/analogs & derivatives , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Alzheimer Disease/physiopathology , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Aniline Compounds/pharmacology , Animals , Astrocytes/cytology , Astrocytes/drug effects , Astrocytes/metabolism , Cognition/drug effects , Cognition/physiology , Culture Media, Conditioned/pharmacology , Disease Models, Animal , Gene Expression Regulation , Genes, Reporter , Hippocampus/drug effects , Hippocampus/metabolism , Hippocampus/pathology , Humans , Liver X Receptors/agonists , Liver X Receptors/metabolism , Luciferases/genetics , Luciferases/metabolism , Male , Memory, Short-Term/drug effects , Memory, Short-Term/physiology , Mice , Mice, Transgenic , Microglia/cytology , Microglia/drug effects , Microglia/metabolism , Neuroprotective Agents/isolation & purification , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/metabolism , Plaque, Amyloid/genetics , Plaque, Amyloid/metabolism , Plaque, Amyloid/physiopathology , Signal Transduction , Stigmasterol/isolation & purification , Stigmasterol/pharmacology , Thiazoles/pharmacologyABSTRACT
In species of the genus Nicotiana, as in most plants, the important polyamine precursor putrescine can be derived from the amino acids ornithine and/or arginine via the activity of ornithine decarboxylase (ODC) and/or arginine decarboxylase (ADC), respectively. Nicotiana species also utilize putrescine to provide the pyrollidine ring of the defensive alkaloid nicotine and its derivatives. Previous biochemical studies, involving callus tissues cultured in vitro, suggested that the ADC-mediated route to putrescine is used preferentially to provide the putrescine that is utilized for nicotine synthesis in N. tabacum. To ascertain if this is the case in N. tabacum plants, where nicotine synthesis takes place exclusively in roots, we used an antisense approach to diminish ADC activity in transformed roots which were cultured in vitro. Several independent lines were recovered possessing markedly reduced levels of ADC transcript and ADC activity compared to controls. Transcript levels of other genes in this general area of metabolism, including ODC, were not altered as a result of the antisense-mediated downregulation of ADC. Concentrations of nicotine were comparable in antisense-ADC and control hairy root lines throughout most of their respective culture cycles, except at the latter stages of growth when the nicotine content of antisense-ADC hairy root lines was observed to be approximately 20% lower than in controls. Levels of anatabine, the second most abundant alkaloid typically found in N. tabacum, which is not derived from putrescine, were slightly elevated in two antisense-ADC hairy root lines at the latter stages of their culture cycles compared to controls. Comparison of alkaloid levels in leaves of transgenic plants that were regenerated from separate antisense-ADC and control transformed root lines indicated that the former possessed slightly elevated levels of anatabine but did not contain average levels of leaf nicotine that were different from that of controls. Our overall conclusion is that the ADC mediated route to putrescine plays a role, but is not of prime importance, in providing the pyrollidine ring which is used for nicotine synthesis in cultured hairy roots of N. tabacum and in roots of healthy greenhouse-grown plants.
