Metformin Enhances Antioxidant Defenses and Limits Lipid Peroxidation Through the Modulation of Nrf2/KEAP1 Pathway in Hippocampal Neurons Exposed to Amyloid-β Oligomers

Jorge Arriagada and colleagues studied metformin in primary fetal rat hippocampal neurons exposed to soluble amyloid-beta oligomers. Cultures received metformin at 2.5 mM for 24 hours before a 6-hour exposure to amyloid-beta oligomers at 500 nM. Metformin promoted nuclear accumulation of Nrf2 and preserved the Nrf2/KEAP1 profile under amyloid stress. It increased expression and activity of SOD1, SOD2, catalase, and glutathione peroxidase 1/2. It also reduced amyloid-beta-induced lipid peroxidation. The PubMed record does not state N, replicate counts, effect sizes, p values, or confidence intervals. The experiment used rat neurons, not people with Alzheimer disease or healthy older adults. The metformin concentration is pharmacological and may not correspond to human brain exposure. The result supports a cellular redox mechanism that can be tested in animal and human studies. It does not show that metformin prevents dementia, slows biological aging, or improves cognition. It also does not establish that Nrf2 modulation is the only mechanism behind any clinical metformin effect. The finding is mechanistic and early-stage. It should not change metformin use outside approved indications.

Collectively, these findings indicate that Met strengthens neuronal antioxidant defenses and promotes redox resilience under amyloid-associated oxidative stress. Our results support modulation of the Nrf2/KEAP1 pathway as a mechanism contributing to the neuroprotective actions of Met and identify the coordinated enhancement of antioxidant defenses and reduction of lipid peroxidation as key components of neuronal redox resilience against AβOs-induced stress.