Research reportIs there an association between hypercholesterolemia and depression? Behavioral evidence from the LDLr−/− mouse experimental model

•The LDLr−/− mice displayed depressive-like behavior in different behavioral tests.•Depressive-like behavior was correlated with hypercholesterolemia.•We found increased MAO-A and B activity in the hippocampus of LDLr−/− mice.•LDL increased MAO activity and reactive species generation in SH-SY5Y cells.

Although epidemiological studies have reported an association between hypercholesterolemia and mood disorders, there is a lack of data regarding depressive-like behavior in animal models of hypercholesterolemia. To address these questions, we assessed depressive-like behavior and hippocampal and cortical monoaminergic metabolism in three-month-old, low-density lipoprotein receptor knockout (LDLr-/-) and C57BL/6 wild-type mice. The LDLr-/- mice exhibited depressive-like behavior in the sucrose preference test, splash test, and tail suspension test. Increased monoamine oxidase (MAO) A and B activity was evidenced in the hippocampus of LDLr-/- mice. Furthermore, to address whether or not cholesterol modulates MAO activity, we exposed SH-SY5Y human neuroblastoma cells to human isolated low-density lipoprotein (LDL). Notably, LDL increased the activity of MAO-A and stimulated the reactive species generation in vitro. These findings indicate that depressive-like behavior in hypercholesterolemic mice is accompanied by alterations in the monoaminergic metabolism, providing new evidence about the association between hypercholesterolemia and depression.