Alzheimer’s disease (AD) is the most common form of dementia worldwide, being characterized by the deposition of senile plaques, neurofibrillary tangles (enriched in the amyloid beta (Aβ) peptide and hyperphosphorylated tau (p-tau), respectively) and memory loss. Aging, type 2 diabetes (T2D) and female sex (especially after menopause) are risk factors for AD, but their crosslinking mechanisms remain unclear. Most clinical trials targeting AD neuropathology failed and it remains incurable. However, evidence suggests that effective anti-T2D drugs, such as the GLP-1 mimetic and neuroprotector liraglutide, can be also efficient against AD. Thus, we aimed to study the benefits of a peripheral liraglutide treatment in AD female mice. We used blood and brain cortical lysates from 10-month-old 3xTg-AD female mice, treated for 28 days with liraglutide (0.2 mg/kg, once/day) to evaluate parameters affected in AD (e.g., Aβ and p-tau, motor and cognitive function, glucose metabolism, inflammation and oxidative/nitrosative stress). Despite the limited signs of cognitive changes in mature female mice, liraglutide only reduced their cortical Aβ_1–42 levels. Liraglutide partially attenuated brain estradiol and GLP-1 and activated PKA levels, oxidative/nitrosative stress and inflammation in these AD female mice. Our results support the earlier use of liraglutide as a potential preventive/therapeutic agent against the accumulation of the first neuropathological features of AD in females.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately 30 % of the global population. Its progression is commonly linked to excessive hepatic fat accumulation, elevated oxidative stress, and impaired mitochondrial function. Given the central role of mitochondria in cellular energy metabolism and redox balance, mitochondria-targeted bioactive molecules have emerged as a promising strategy for the prevention and treatment of MASLD. To this end, we develop AntiOxBEN₂, a mitochondria-targeted compound generated by conjugating the antioxidant moiety of gallic acid with the lipophilic triphenylphosphonium cation. This design enables selective accumulation of AntiOxBEN₂ in the mitochondrial matrix, taking advantage of the organelle's negative membrane potential. In multiple in vitro disease models, AntiOxBEN₂ has demonstrated remarkable antioxidant properties, effectively mitigating oxidative stress and preserving mitochondrial function. However, effects on cellular and mitochondrial energy metabolism in vivo remain unexplored. In the present study, we tested whether chronic peripheral administration of AntiOxBEN₂ (0.5 or 2.5 mg/kg, 3x/week) could prevent MASLD development in male and female C57BL/6 J mice fed with a 30 % high-fat, 30 % high-sucrose (Western Diet, WD) diet for 16 weeks. Our results demonstrate that AntiOxBEN₂ treatment significantly reduced hepatic lipid accumulation in both sexes without affecting body weight. This reduction was accompanied by improvements in mitochondrial function, including enhanced fatty acid oxidation (FAO) and increased activities of mitochondrial electron transport chain (ETC) complexes. Moreover, AntiOxBEN₂ administration lowered circulating levels of hepatic damage markers (ALT and AST), as well as insulin and leptin. Notably, a clear sexual dimorphism was observed, with female mice displaying a more pronounced improvement in mitochondrial parameters. Collectively, these findings highlight the therapeutic potential of AntiOxBEN₂ for the prevention and/or treatment of MASLD.