Obesity-induced cofilin1 pathway dysregulation: Possible molecular links between neuroinflammation, cognitive decline, and Alzheimer's disease biomarkers

Obesity is a growing concern globally, particularly among young populations. Cofilin1, a major actin-depolymerizing factor (ADF) isoform in the CNS, acts as a stress protein that triggers neuroinflammation and correlates with the onset of Alzheimer's disease (AD). However, its role in obesity has not yet been identified. In this study, we investigated the influence of diet-induced obesity on cofilin1 dysregulation in the brain and its correlation to neurobehavioral deficiencies, neuroinflammation, synaptic dysfunction, and AD biomarkers. Male C57BL/6 mice were fed a regular diet (control) or a high-fat diet (HFD, obese) for 7 weeks to induce obesity. Our data demonstrate that the activation of cofilin1 in the hippocampus region of HFD mice brains is mediated by Slingshot homolog-1 (SSH1) overactivation and LIM kinase-1 (LIMK1) inactivation. However, pcofilin1 is also increased, but this increase might be mediated by mechanisms other than an actin-dependent mechanism. Cofilin1 pathway dysregulation in HFD-fed mice was correlated with cognitive decline, as assessed using the Morris water maze (MWM) and Y-maze, and increased astrocytic activation protein and synaptotoxicity by downregulating pre- and post-synaptic markers. It also correlates with the significant upregulation of AD biomarkers (pTau_Ser396) in the brain, saliva, and serum. At the systemic level, our results showed dysregulation of the gut microbiota, characterized by a ∼53 % increase in the Firmicutes: Bacteroidetes ratio in HFD-fed mice. HFD-fed mice also exhibited a significant increase in certain inflammatory and anti-inflammatory blood cytokines. Our findings suggest that active cofilin1 plays a significant role in diet-induced obesity and may become a potential therapeutic target.