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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 . |
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