(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Memory-Disorders

Alzheimer's disease (AD) is one of the severe chronic diseases characterized with amyloid beta (Aβ) aggregation and formation of senile-plaque (SP) like structures. Numerous risk factors including trace metals and cholesterol in diet have been identified as potential players for the onset of Aβ aggregation. To further illustrate the effects of copper and cholesterol in AD pathology, we employed an AD model mouse strain (Tg2567) and examined the histological and biochemical changes in the mouse brains and blood. When supplied with 0.1 mg/L copper in drinking water and 2% cholesterol in the food, the mice showed significant deposit of amyloid beta (Aβ) and SP plaque formation in hippocampus and temporal cortex regions in their brains. These mice also showed elevated superoxide dismutase (SOD) activity and increased ceruloplasmin (CP) concentration, and reduced glutathione peroxidase (Gpx) activity in the blood. The physiological function tests indicated these mice were significantly impeded on learning and memory. We further examined the counteracting effects of 0.1 mg/L zinc and 1.0 mg/L fluvastatin (Cholesterol-lowering drug). The combination of zinc and fluvastatin effectively reversed the copper/cholesterol caused memory loss, anatomic amyloid deposits and the biochemical changes in the blood. This work provides more evidence of high-level cholesterol and copper as risk factors to trigger amyloid aggregation and mental dementia; zinc and reduction of food cholesterol levels can protect the animals from amyloid accumulation and learning impairment. The beneficial outcomes of zinc and fluvastatin could hint some potential usages in preventive measures for high-risk AD individuals, but further rigorous test are needed.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Animals; Brain; Cholesterol; Cholesterol, Dietary; Copper; Disease Models, Animal; Fluvastatin; Male; Memory Disorders; Mice; Plaque, Amyloid; Zinc

Alzheimer's disease (AD), the most common cause of dementia in the elderly, is characterized by amyloid beta (Abeta)-containing plaques and neurofibrillary tangles, and synaptic and neuronal loss, along with progressive cognitive impairment. Although growing evidence suggests the beneficial effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) on AD, this notion is still controversial. To evaluate the efficacy of statins for Abeta-induced cognitive impairment, we employed an Abeta injection model. Using this model, the present study demonstrated that pretreatment with fluvastatin, but not post-treatment just after Abeta exposure, prevented Abeta-induced memory impairment. We also observed that fluvastatin significantly decreased Abeta accumulation and oxidative stress after Abeta injection. Mice treated with simvastatin, but not fluvastatin, did not demonstrate the prevention of Abeta-induced memory impairment, and showed no significant decrease in oxidative stress. More importantly, fluvastatin significantly prevented the loss of neurons in the basal forebrain induced by Abeta. Overall, the present study demonstrated that fluvastatin significantly prevented memory impairment induced by Abeta. The beneficial effects of fluvastatin might be explained by the preservation of neurons through a significant decrease in Abeta accumulation and oxidative stress. In clinical practice, the timing of the start of fluvastatin treatment might be critical in achieving a beneficial effect on cognitive function.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Animals; Behavior, Animal; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Male; Memory Disorders; Mice; Oxidative Stress; Simvastatin