Metformin Ameliorates Cognitive Deficits and Neuroinflammation in a Mouse Model of Familial Hypercholesterolemia

Familial hypercholesterolemia (FH), caused by mutations in the low-density lipoprotein receptor (LDLr) gene, has been increasingly associated with neurodegenerative and mood disorders. Studies with LDLR knockout mice (LDLr^-/-) showed that neuroinflammation is a key event in FH-related brain dysfunction. Because mTOR inhibition has been shown to mitigate brain alterations in this model, we hypothesized that metformin, a drug reported to influence cellular energy metabolism, could attenuate FH-associated brain changes. To test this, adult LDLr^-/- mice received daily oral doses of metformin (200 mg/Kg) or vehicle for 30 days. During the final week, behavioral assessments were conducted, including the open-field test, novel object recognition and object reallocation tasks, and the tail suspension test (depressive-like behavior). Body weight, total cholesterol and glucose plasma levels were analyzed. Hippocampal astrocyte and microglial density, as well as the expression of genes related to neuroinflammation and synaptic plasticity, were evaluated. Metformin did not alter total cholesterol levels but significantly improved cognitive performance and reduced depressive-like behavior. The treatment also attenuated hippocampal astrogliosis without affecting microglial reactivity. Molecular analysis revealed reduced hippocampal TGF-β gene expression and increased PSD-95 gene expression and protein content in metformin-treated LDLr^-/- mice. Although a slight, non-significant reduction in the phosphorylated-to-total mTOR ratio was detected, no clear evidence of AMPK/mTOR pathway modulation was observed. Overall, metformin improved memory function and astrocyte reactivity in LDLr^-/- mice independently of cholesterol reduction and without demonstrable involvement of the AMPK/mTOR pathway, suggesting its potential as a therapeutic strategy for FH-associated brain dysfunction.