Polyphenols as Modulators of Fibrinogen-Driven Neuroinflammation: Implications for Neurodegenerative Disease Prevention

Polyphenols are natural compounds found in a variety of plants and are widely recognized for their antioxidant properties and potential health benefits, particularly in relation to inflammation and neuroprotection. Among these, oleuropein aglycone (OleA) and its main metabolite hydroxytyrosol (HT) from extra virgin olive oil (EVOO) and olives have the potential to counteract pro-inflammatory signals in the brain, including those triggered by fibrinogen, a key protein involved in blood clotting. Fibrinogen is known to activate microglia, the resident immune cells of the central nervous system, leading to the production of inflammatory cytokines that exacerbate neuroinflammatory conditions.

The aim of our study was to enhance the understanding of the molecular mechanisms underlying the protective effects of EVOO polyphenols at different concentrations on fibrinogen-induced damage by conducting in vitro experiments using the human microglia C13NJ and SH-SY5Y neuronal cell models, where cellular viability and oxidative stress were assessed. Additionally, immunofluorescence analysis was performed to measure the levels of neuroinflammatory markers, and we investigated the mitochondrial efficiency in microglia and neuronal cells treated with C13NJ-conditioned medium.

Our results indicate that both OleA and HT prevent the activation of TRL4 and p-NF-κB and the release of pro-inflammatory chemokines and cytokines, as evidenced by conditioned medium treatments on SH-SY5Y cells. Moreover, OleA and HT promote an increase in TREM2 levels and act as epigenetic modulators on histone 4 lactylation while also increasing the mitochondrial function.

The ability of OleA and HT to promote an anti-inflammatory microglial phenotype positions them as promising molecules for reducing neuroinflammation, protecting neurons from damage, and supporting overall brain health. Dietary or supplemental strategies incorporating these polyphenols could provide preventive approaches and strategies aimed at mitigating inflammation before the onset of neurodegenerative diseases. Additionally, they may serve as complementary therapies to existing treatments that focus on managing neuroinflammation and supporting neuronal health.