phytosterols and Dementia

As the aging of the world's population is becoming increasingly serious, dementia-related diseases have become a hot topic in public health research. In recent years, human epidemiological studies have focused on lipid metabolism disorders and dementia. The efficacy of phytosterol intake as a cholesterol-lowering agent has been demonstrated. Phytosterols directly serve as ligands of the nuclear receptors, peroxisome proliferator-activated receptors (PPARs), activating Sirtuin 1 (SIRT-1), which are involved in the regulation of lipid metabolism and the pathogenesis of dementia. Moreover, phytosterols mediate cell and membrane cholesterol efflux or beta amyloid (Aβ) metabolism, which have preventative and therapeutic effects on dementia. Additionally, incorporation of plant sterols in lipid rafts can effectively reduce dietary fat and alter the dietary composition of fiber, fat and cholesterol to regulate appetite and calories. Overall, the objectives of this review are to explore whether phytosterols are a potentially effective target for the prevention of dementia and to discuss a possible molecular mechanism by which phytosterols play a role in the pathogenesis of dementia via the PPARs-SIRT-1 pathway.

Topics: Animals; Anticholesteremic Agents; Cholesterol; Dementia; Diet; Dietary Fats; Disease Models, Animal; Homeostasis; Humans; Lipid Metabolism; Peroxisome Proliferator-Activated Receptors; Phytosterols; Sirtuin 1

The factors responsible for ALS-parkinsonism dementia complex (ALS-PDC), the unique neurological disorder of Guam, remain unresolved, but identification of causal factors could lead to clues for related neurodegenerative disorders elsewhere. Earlier studies focused on the consumption and toxicity of the seed of Cycas circinalis, a traditional staple of the indigenous diet, but found no convincing evidence for toxin-linked neurodegeneration. We have reassessed the issue in a series of in vitro bioassays designed to isolate non-water soluble compounds from washed cycad flour and have identified three sterol beta-d-glucosides as potential neurotoxins. These compounds give depolarizing field potentials in cortical slices, induce alterations in the activity of specific protein kinases, and cause release of glutamate. They are also highly toxic, leading to release of lactate dehydrogenase (LDH). Theaglycone form, however, is non-toxic. NMDA receptor antagonists block the actions of the sterol glucosides, but do not compete for binding to the NMDA receptor. The most probable mechanism leading to cell death may involve glutamate neuro/excitotoxicity. Mice fed cycad seed flour containing the isolated sterol glucosides show behavioral and neuropathological outcomes, including increased TdT-mediated biotin-dUTP nick-end labelling (TUNEL) positivity in various CNS regions. Astrocytes in culture showed increased caspase-3 labeling after exposure to sterol glucosides. The present results support the hypothesis that cycad consumption may be an important factor in the etiology of ALS-PDC and further suggest that some sterol glucosides may be involved in other neurodegenerative disorders.

Topics: Amyotrophic Lateral Sclerosis; Animals; Astrocytes; Biological Assay; Cells, Cultured; Cerebral Cortex; Cholesterol; Cycas; Dementia; Glucose; Glucosides; Guam; Humans; In Vitro Techniques; Male; Mice; Neurons; Neurotoxins; Parkinsonian Disorders; Patch-Clamp Techniques; Phytosterols; Plant Extracts; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seeds; Sitosterols; Stigmasterol