amyloid-beta-peptides and Hypercholesterolemia

Epidemiological studies suggest that statins reduce the risk of developing Alzheimer disease. Cell and animal experiments have revealed a connection between cholesterol metabolism and the processing of amyloid precursor protein. To our knowledge, the mechanism for statins in risk reduction of Alzheimer disease is unknown.. To test the effect of statin treatment on beta-amyloid (A beta) metabolism in humans.. A prospective, randomized, dose-finding 36-week treatment trial with statins. Plasma samples were taken at baseline (week 0) and at weeks 6, 12, and 36.. Outpatient clinical study at a university hospital.. Thirty-nine patients who met the criteria for hypercholesterolemia.. Patients were randomized to oral treatment with either simvastatin or atorvastatin calcium according to the following regimen: simvastatin, 40 mg/d, or atorvastatin, 20 mg/d, for 6 weeks; followed by simvastatin, 80 mg/d, or atorvastatin, 40 mg/d, for 6 weeks; and finally, simvastatin, 80 mg/d, or atorvastatin, 80 mg/d, for 24 weeks.. Plasma levels of A beta(1-40) and A beta(1-42) were measured using 2 enzyme-linked immunosorbent assays, and total A beta was quantified by Western blotting.. Treatment with both statins reduced total plasma cholesterol levels by 56% (P =.00). The plasma levels of A beta(1-40), A beta(1-42), and total A beta were stable in individual patients during the treatment period. No significant change in the level of A beta(1-40), A beta(1-42), or total A beta was found.. This study questions the effect of statins on the processing of amyloid precursor protein in humans.

Topics: Adult; Aged; Amyloid beta-Peptides; Anticholesteremic Agents; Atorvastatin; Cross-Over Studies; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Female; Heptanoic Acids; Humans; Hypercholesterolemia; Lipids; Male; Middle Aged; Peptide Fragments; Prospective Studies; Pyrroles; Simvastatin; Time Factors

High cholesterol aggravates the risk development of Alzheimer's disease (AD). AD is closely related to the transport impairment of Amyloid-β (Aβ) in the blood-brain barrier. It is unclear whether high cholesterol affects the risk of cognitive impairment in AD by affecting Aβ transport. The purpose of the study is to investigate whether high cholesterol regulates Aβ transport through low-density Lipoprotein Receptor-Related Protein 1 (LRP1) and Receptor for Advanced Glycation End products (RAGE) in the risk development of AD.. We established high cholesterol AD mice model. The learning and memory functions were evaluated by Morris Water Maze (MWM). Cerebral microvascular endothelial cells were isolated, cultured, and observed. The expression levels of LRP1 and RAGE of endothelial cells and their effect on Aβ transport in vivo were observed. The expression level of LRP1 and RAGE was detected in cultured microvessels after using Wnt inhibitor DKK-1 and β-catenin inhibitor XAV-939.. Hypercholesterolemia exacerbated spatial learning and memory impairment. Hypercholesterolemia increased serum Aβ40 level, while serum Aβ42 level did not change significantly. Hypercholesterolemia decreased LRP1 expression and increased RAGE expression in cerebral microvascular endothelial cells. Hypercholesterolemia increased brain apoptosis in AD mice. In in vitro experiment, high cholesterol decreased LRP1 expression and increased RAGE expression, increased Aβ40 expression in cerebral microvascular endothelial cells. High cholesterol regulated the expressions of LRP1 and RAGE and transcriptional activity of LRP1 and RAGE promoters by the Wnt/β-catenin signaling pathway.. High cholesterol decreased LRP1 expression and increased RAGE expression in cerebral microvascular endothelial cells, which led to Aβ transport disorder in the blood-brain barrier. Increased Aβ deposition in the brain aggravated apoptosis in the brain, resulting to cognitive impairment of AD mice.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Brain; Cholesterol; Disease Models, Animal; Endothelial Cells; Humans; Hypercholesterolemia; Low Density Lipoprotein Receptor-Related Protein-1; Mice; Peptide Fragments; Receptor for Advanced Glycation End Products

Recent findings suggest that hypercholesterolemia may contribute to the onset of Alzheimer's disease-like dementia but the underlying mechanisms remain unknown. In this study, we evaluated the cognitive performance in rodent models of hypercholesterolemia in relation to neuroinflammatory changes and amyloid precursor protein (APP) processing, the two key parameters of Alzheimer's disease pathogenesis. Groups of normal C57BL/6 and low density lipoprotein receptor (LDLR)-deficient mice were fed a high fat/cholesterol diet for an 8-week period and tested for memory in a radial arm maze. It was found that the C57BL/6 mice receiving a high fat diet were deficient in handling an increasing working memory load compared with counterparts receiving a control diet while the hypercholesterolemic LDLR-/- mice showed impaired working memory regardless of diet. Immunohistochemical analysis revealed the presence of activated microglia and astrocytes in the hippocampi from high fat-fed C57BL/6 mice and LDLR-/- mice. Consistent with a neuroinflammatory response, the hyperlipidemic mice showed increased expression of cytokines/mediators including tumor necrosis factor-alpha, interleukin-1beta and -6, nitric oxide synthase 2, and cycloxygenase 2. There was also an induced expression of the key APP processing enzyme i.e. beta-site APP cleaving enzyme 1 in both high fat/cholesterol-fed C57BL/6 and LDLR-/- mice accompanied by an increased generation of C-terminal fragments of APP. Although ELISA for beta-amyloid failed to record significant changes in the non-transgenic mice, a threefold increase in beta-amyloid 40 accumulation was apparent in a strain of transgenic mice expressing wild-type human APP on high fat/cholesterol diet. The findings link hypercholesterolemia with cognitive dysfunction potentially mediated by increased neuroinflammation and APP processing in a non-transgenic mouse model.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Brain; Cholesterol; Cytokines; Dietary Fats; Disease Models, Animal; Encephalitis; Hypercholesterolemia; Maze Learning; Memory Disorders; Memory, Short-Term; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons; Peptide Fragments; Receptors, LDL; Up-Regulation