Genetic Reduction of Cholesterol Synthesis in the Mouse Brain Does Not Affect Amyloid Formation in an Alzheimer’s Disease Model, but Does Extend Lifespan
dc.contributor.advisor | Russell, David W. | en |
dc.creator | Warren, Rebekkah Lynn | en |
dc.date.accessioned | 2011-08-26T17:35:30Z | en |
dc.date.accessioned | 2014-02-19T22:02:59Z | |
dc.date.available | 2011-08-26T17:35:30Z | en |
dc.date.available | 2014-02-19T22:02:59Z | |
dc.date.issued | 2011-08-26T17:35:30Z | en |
dc.description.abstract | In vitro alterations in cellular cholesterol content or synthesis affect the cleavage of amyloid precursor protein (APP) to amyloidogenic peptides characteristic of Alzheimer’s disease (AD). To determine whether a decrease in cholesterol synthesis would affect APP processing in vivo, we crossed cholesterol 24-hydroxylase knockout (KO) mice, which exhibit a 50 percent reduction in sterol synthesis, with transgenic mice (B6.Cg-Tg(APPswe, PSEN1E9)85Dbo/J) that develop AD and followed progression of the disease and lipid metabolism in the offspring. APP expression and amyloid plaque deposition in the cortex and hippocampus of 3- to 15-month-old male and female AD mice were similar in the presence and absence of cholesterol 24-hydroxylase. At 15 months of age, a modest but statistically significant decline in insoluble A-beta 40 and A-beta 42 peptide levels was detected in the hippocampus but not cortex of KO/AD mice versus WT/AD mice. Amyloid plaque accumulation did not affect brain sterol or fatty acid synthesis rates in 24-hydroxylase WT or KO mice. Unexpectedly, loss of one or two 24-hydroxylase alleles increased longevity in AD mice. These studies suggest that reducing de novo cholesterol synthesis in the brain will not substantially alter the course of AD, but may confer a survival advantage. | en |
dc.identifier.other | en | |
dc.identifier.uri | http://hdl.handle.net/2152.5/891 | en |
dc.language.iso | en | en |
dc.subject | Amyloid beta-Protein Precursor | en |
dc.subject | Alzheimer Disease | en |
dc.subject | Lipid Metabolism | en |
dc.title | Genetic Reduction of Cholesterol Synthesis in the Mouse Brain Does Not Affect Amyloid Formation in an Alzheimer’s Disease Model, but Does Extend Lifespan | en |
dc.type | Thesis | en |
thesis.degree.grantor | Graduate School of Biomedical Sciences | en |
thesis.degree.level | Ph.D. | en |
thesis.degree.name | Doctor of Philosophy | en |