Sex- and age-dependent mitochondrial dysfunction and cognitive impairment in a mouse model of familial hypercholesterolemia

BACKGROUND: Familial hypercholesterolemia (FH) is a genetic disorder of cholesterol metabolism caused by loss-of-function variants in the low-density lipoprotein receptor (LDLR), resulting in persistently elevated LDL-cholesterol levels in plasma. Although hypercholesterolemia, especially the high levels of LDL, has been linked to an increased risk of dementia, the underlying mechanisms remain unclear. Here, we investigated the effects of sexual dimorphism and aging on metabolic and cognitive functions in a murine model of FH. METHODS: mice were used in this study. Behavioral assessments included locomotor activity, spatial memory, and anxiety-like behavior. Plasma lipid profiles were measured, and mitochondrial function in the hippocampus and brown adipose tissue (BAT) was assessed using high-resolution respirometry. RESULTS: mice regardless of sex or age. Hippocampal oxygen consumption was reduced in adult males and middle-aged female mice, whereas BAT respiration was impaired in both sexes at middle-aged animals, affecting distinct respiratory parameters. Correlation analyses revealed that elevated cholesterol levels were associated with memory deficits and hyperlocomotion, along with positive correlations between hippocampal and BAT mitochondrial function. CONCLUSIONS: Collectively, these findings demonstrate that FH induces sex- and age-dependent alterations in behavior and mitochondrial metabolism, providing mechanistic insights into the link between FH and neurodegenerative disease risk.