AGE- AND ALZHEIMER’S DISEASE–DEPENDENT ALTERATIONS OF LEPTIN SIGNALING IN THE BRAINSTEM

Physiological aging (PA) and Alzheimer’s disease (AD) are associated with progressive metabolic dysregulation, including central leptin resistance, a key anorexigenic hormone regulating energy homeostasis. While hypothalamic alterations have been widely described, the involvement of brainstem nuclei remains poorly characterized. Given the role of the brainstem in integrating anorexigenic and orexigenic signals, we hypothesized that PA and AD impair brainstem leptin responsiveness. The main objective of this study was to characterize brainstem leptin signaling during PA and AD progression in WT mice aged 3, 6, and 12 months, and in the 5xFAD model of AD. Leptin was administered intracerebroventricularly, and activation of early signaling pathways was analyzed by Western blot. Protein and gene expression of the leptin receptor (LEPR) and key downstream mediators, including STAT3, Akt, and AMPK, were assessed by Western blot and/or RT-qPCR. LEPR expression and distribution were also analyzed by immunohistochemistry in distinct brainstem nuclei involved in energy homeostasis. We observed a significant age-dependent reduction in brainstem leptin responsiveness in both WT and 5xFAD mice. Alterations in early leptin signaling events were detected in both genotypes, occurring earlier and with greater severity in 5xFAD mice. Aging and genotype were also associated with changes in LEPR expression across specific brainstem nuclei and alterations of LEPR signaling pathway in the brainstem. These findings demonstrate that the brainstem develops leptin resistance during PA, which is exacerbated and accelerated in AD. Brainstem leptin signaling dysfunction may contribute to age- and AD-related metabolic alterations, identifying this region as a potential therapeutic target.