Reduction of cholesterol synthesis in the mouse brain does not affect amyloid formation in Alzheimer's disease, but does extend lifespan.
Alterations in cellular cholesterol synthesis or content in cultured neurons affect the cleavage of amyloid precursor protein to amyloidogenic Abeta(40) and Abeta(42) peptides characteristic of Alzheimer's disease. To determine whether a decrease in cholesterol synthesis affects amyloid precursor protein processing in vivo, we crossed cholesterol 24-hydroxylase knockout mice, which exhibit a 50% reduction in brain sterol synthesis, with transgenic mice [B6.Cg-Tg(APPswe, PSEN1E9)85Dbo/J] that develop Alzheimer's disease-like pathology. Amyloid precursor protein expression and amyloid plaque deposition in the cortex and hippocampus of male and female Alzheimer's disease mice between the ages of 3 to 15 months were similar in the presence and absence of cholesterol 24-hydroxylase. A modest but statistically significant decline in insoluble Abeta(42) peptide levels was detected in the hippocampus of 12-month-old knockout/Alzheimer's disease males. The levels of insoluble Abeta(40) and Abeta(42) peptides in 15-month-old knockout/Alzheimer's disease females were also reduced slightly. Although amyloid plaque accumulation did not affect brain sterol or fatty acid synthesis rates in 24-hydroxylase WT or knockout mice, loss of one or both cholesterol 24-hydroxylase alleles increased longevity in Alzheimer's disease mice. These studies suggest that reducing de novo cholesterol synthesis in the brain will not substantially alter the course of Alzheimer's disease, but may confer a survival advantage.
Halford
Rebekkah W
RW
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Russell
David W
DW
D000544:Alzheimer Disease / Q000378:metabolism*; D000682:Amyloid / Q000378:metabolism*; D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis*; D000072556:Cholesterol 24-Hydroxylase; D005260:Female; D008136:Longevity / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
D000682:Amyloid; D010446:Peptide Fragments; D002784:Cholesterol; D013250:Steroid Hydroxylases; D000072556:Cholesterol 24-Hydroxylase