Agomelatine drives sex-specific neuroprotection and reduced pathology in rat and human Alzheimer’s models

Alzheimer's disease (AD) remains without effective disease-modifying therapies, underscoring the need for interventions that target interconnected molecular and cellular processes driving cognitive decline. Leveraging a cross-species translational framework integrating a progressive rat model of Alzheimer's disease with human iPSC-derived neurons carrying familial AD mutations, we identify agomelatine (AGO) as a disease-modifying candidate. A clinically used melatonergic agonist and 5-HT _2C serotonergic antagonist, we found that AGO acts as a sex-selective modulator of AD-related neuronal and microglial dysfunction with therapeutic relevance across species. TgF344-AD rats and their wildtype littermates received chronic dietary AGO (∼10 mg/kg/day) from 5 to 11 months of age and underwent hippocampal-dependent spatial learning assessment, quantitative hippocampal histopathology, and bulk RNA sequencing to evaluate the therapeutic effect on cognition, pathology, and molecular mechanisms. Human isogenic iPSC-derived cortical neurons carrying PSEN2 ^N141I or APPV ^717I mutations were treated with 20 µM AGO followed by bulk RNA sequencing, to define AGO-driven transcriptional pathway modulation in AD neurons In TgF344-AD rats, AGO produced robust female-specific benefits. AGO selectively restored hippocampal-dependant cognitive performance in female but not male transgenic rats. These improvements were independent of amyloid burden and instead aligned with reductions in microgliosis and pathogenic AT8-positive tau phosphorylation. Additionally, AGO normalized reactive and amoeboid microglial states exclusively in females and enhanced doublecortin-defined neurogenesis without altering mature NeuN⁺ neuronal density. This coordinated hippocampal stabilization highlights AGO's capacity to restore plasticity rather than simply suppress pathology. Transcriptomic analyses revealed sex-divergent mechanisms underlying these effects. In females, AGO activated metabolic, oxygen-handling, lipid-processing, neuroimmune, and CREB/IGF-1 signaling pathways while suppressing ER-stress, epigenetic, and ion-channel transcripts, changes consistent with resilience-promoting cellular reprogramming. In males, AGO preferentially modulated mitochondrial redox biology, transcriptional regulators, and extracellular matrix components. Despite these differences, both sexes showed AGO-induced engagement of conserved AD-relevant pathways, including shared induction of synaptic plasticity and hemoglobin/oxygen-transport related genes, suggesting a convergent neuroprotective molecular signature. To translate these findings to a human system, we examined AGO's effects in PSEN2 ^N141I and APP ^V717I iPSC-derived cortical neurons. Both mutations produced convergent deficits in synaptic integrity, neuronal maturity, trophic signaling, proteostasis, metabolism, and excitability, alongside dysregulated developmental and ECM-remodeling programs. AGO partially reversed these pathogenic transcriptional changes, up-regulating synaptic, metabolic, vesicle-trafficking, and redox-stress resilience genes while suppressing pathological developmental and inflammatory pathways, demonstrating conserved engagement of neuronal recovery programs. Together, these results identify AGO as a promising non-amyloid therapeutic candidate capable of modulating AD-relevant pathways in rodents and human models. The sex-selective efficacy observed <i>in vivo</i> , combined with conserved transcriptional responses across species, underscores the translational relevance of AGO-driven molecular reprogramming in AD.