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.