Increased Levels of 27-Hydroxycholesterol Induced by Dietary Cholesterol in Brain Contribute to Learning and Memory Impairment in Rats.

SCOPE: Dietary cholesterol has been shown to play a role in the development of Alzheimer's disease (AD). It is proposed that oxysterol especially 27-hydroxycholesterol (27-OHC) may play a potential role in β-amyloid peptides (Aβ) production and accumulation during AD progression.

METHODS AND RESULTS: To investigate the mechanisms of dietary cholesterol and 27-OHC on learning and memory impairment, male Sprague-Dawley rats are fed with cholesterol diet with or without 27-OHC synthetase inhibitor (anastrozole) injection. The levels of cholesterol, 27-OHC, 24-hydroxycholesterol (24S-OHC), 7α-hydroxycholesterol, and 7β-hydroxycholesterol in plasma are determined; apolipoprotein A (ApoA), apolipoprotein B (ApoB), HDL-cholesterol (HDL-C), and LDL-cholesterol (LDL-C) in plasma or brain; CYP27A1 and CYP7A1 in liver and CYP46A1 and CYP7B1 in brain; cathepsin B, cathepsin D, and acid phosphatase in lysosome; and Aβ1-40 and Aβ1-42 in brain. Results show increased levels of 27-OHC (p < 0.01), LDL-C (p < 0.01), and ApoB (p < 0.01), and decreased level of HDL-C (p < 0.05) in plasma, upregulated CYP27A1 (p < 0.01) and CYP7A1 (p < 0.01) expression in liver, altered lysosomal function, and increased level of Aβ in brain (p < 0.05).

CONCLUSIONS: This study indicates that the mechanisms of dietary cholesterol on learning and memory impairment may be involved in cholesterol metabolism and lysosome function with the increase of plasma 27-OHC, thus resulting in Aβ formation and accumulation.