Age- and sex-associated alterations in hypothalamic mitochondrial bioenergetics and inflammatory-associated signaling in the 3xTg mouse model of Alzheimer’s disease

Mitochondrial dysfunction and associated inflammatory signaling are pivotal in both aging and in Alzheimer’s disease (AD). Studies have also shown that hypothalamic function is affected in AD. The hypothalamus may be a target for AD drugs given that mitochondrial alterations are observed in the hypothalamus. This study investigated how age and sex affect mitochondrial bioenergetics and inflammatory signaling in the hypothalamic mitochondria of 3xTg and control mice at 2, 6, and 13 months, aiming to enhance our understanding of these processes in aging and AD. Parameters included oxygen consumption rates, expression levels of subunits comprising mitochondrial complexes I-V, the enzymatic activity of cytochrome c oxidase (COX), transcription factors associated with inflammation such as NF-κB, pIκB-α, Nrf2, and other inflammatory biomarkers. Hypothalamic mitochondrial dysfunction was observed in 3xTg females as early as 2 months, but no changes were detected in 3xTg males until 6 months of age. In 3xTg mice, subunit expression levels for mitochondrial complexes I-II were significantly reduced in both sexes. Significant sex-based differences in COX activity were also observed at 13 months of age, with levels being lower in females compared to males. In addition, significant sex differences were indicated in NF-κB, pIκB-α, Nrf2, and other inflammatory biomarkers at different age groups during normal aging and AD progression. These findings highlight important sex differences in hypothalamic bioenergetics and inflammation, offering insights into potential new targets for preventing and/or treating AD.