Biochemistry, Cell Biology, Cellular and Molecular Neuroscience
7
Scopus Publications
Scopus Publications
Metformin Ameliorates Cognitive Deficits and Neuroinflammation in a Mouse Model of Familial Hypercholesterolemia Natália Baltazar do Nascimento, Hémelin Resende Farias, Tainá Schons, Alex Paulo Zeferino Padilha, Mariana Viana Costa, et al. Neurochemical Research, 2026 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.
Microglia contribute to cognitive decline in hypercholesterolemic LDLr−/− mice Matheus Scarpatto Rodrigues, Natalia Baltazar do Nascimento, Hemelin Resende Farias, Taina Schons, Alessandra Gonçalves Machado, et al. Journal of Neurochemistry, 2024 Familial hypercholesterolemia (FH) is caused by mutations in the gene that encodes the low‐density lipoprotein (LDL) receptor, which leads to an excessive increase in plasma LDL cholesterol levels. Previous studies have shown that FH is associated with gliosis, blood–brain barrier dysfunction, and memory impairment, but the mechanisms associated with these events are still not fully understood. Therefore, we aimed to investigate the role of microgliosis in the neurochemical and behavioral changes associated with FH using LDL receptor knockout (LDLr−/−) mice. We noticed that microgliosis was more severe in the hippocampus of middle‐aged LDLr−/− mice, which was accompanied by microglial morphological changes and alterations in the immunocontent of synaptic protein markers. At three months of age, the LDLr−/− mice already showed increased microgliosis and decreased immunocontent of claudin‐5 in the prefrontal cortex (PFC). Subsequently, 6‐month‐old male C57BL/6 wild‐type and LDLr−/− mice were treated once daily for 30 days with minocycline (a pharmacological inhibitor of microglial cell reactivity) or vehicle (saline). Adult LDLr−/− mice displayed significant hippocampal memory impairment, which was ameliorated by minocycline treatment. Non‐treated LDLr−/− mice showed increased microglial density in all hippocampal regions analyzed, a process that was not altered by minocycline treatment. Region‐specific microglial morphological analysis revealed different effects of genotype or minocycline treatment on microglial morphology, depending on the hippocampal subregion analyzed. Moreover, 6‐month‐old LDLr−/− mice exhibited a slight but not significant increase in IBA‐1 immunoreactivity in the PFC, which was reduced by minocycline treatment without altering microglial morphology. Minocycline treatment also reduced the presence of microglia within the perivascular area in both the PFC and hippocampus of LDLr−/− mice. However, no significant effects of either genotype or minocycline treatment were observed regarding the phagocytic activity of microglia in the PFC and hippocampus. Our results demonstrate that hippocampal microgliosis, microglial morphological changes, and the presence of these glial cells in the perivascular area, but not increased microglial phagocytic activity, are associated with cognitive deficits in a mouse model of FH.image
