Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 9, Pages 3502-3506Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0813349106
Keywords
amyloid plaque; cholesterol 24-hydroxylase; P450; statin
Categories
Funding
- National Institutes of Health Research [HL20948, DK81182]
- Robert A. Welch Foundation [I-0971]
Ask authors/readers for more resources
Alterations in cellular cholesterol synthesis or content in cultured neurons affect the cleavage of amyloid precursor protein to amyloidogenic A beta(40) and A beta(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 A beta(42) peptide levels was detected in the hippocampus of 12-month-old knockout/Alzheimer's disease males. The levels of insoluble A beta(40) and A beta(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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available