In Vivo and In Silico Evidence: Hippocampal Cholesterol Metabolism Decreases with Aging and Increases with Alzheimers Disease -- Modeling Brain Aging and Disease

摘要

Genome wide association studies revealed genetic evidence for involvement of cholesterol metabolism in the etiology of Alzheimers disease (AD). The present study used gene expression profiles on human Cornu Ammonis 1(CA1) for subjects with severe AD and an age-matched group to determine the enzyme reaction rate constants for 16 core metabolic pathways including cholesterol biosynthesis, isoprenoid production, and cholesterol catabolism for removal from brain. The core metabolic model was used to simulate a young hippocampus (20-39yo) to compare with age-matched control group for our AD study (mean= 85.3y). In the aged human brain, the flux through the rate limiting step in the simulation for aged human hippocampus was lower by 9.5%, the cholesterol level was 52.3% lower in the simulation and 33.6% lower in the aged human brain, validating the in silico method. Data was also used to evaluate sterol regulatory element binding protein 1 and 2 (SREBP1 & SREBP2) showing the levels were increased significantly in the severe AD samples versus age-matched control. We predicted that the core metabolism simulation of severe AD versus age-matched control would show corresponding results and they do. The sensitivities analyses for incipient and severe AD demonstrated how they differ: Most reactions are insensitive for severe AD and two sensitive peaks are obvious, cholesterol and ubiquinone levels are most sensitive to cholesterol 24-hydroxylase, CYP46a1. These findings are consistent with statins being ineffective in clinical trials for treatment of AD, post-diagnosis.