Early Hypothalamic Aromatase Loss Is Associated with Neuronal Insulin-Resistance Signaling During Progression of Experimental Alzheimer’s Disease

Alzheimer’s disease (AD) is increasingly recognized as a neurodegenerative disorder characterized by central insulin resistance and cerebral hypometabolism. The steroid hormone, 17β-estradiol (E2), interacts closely with insulin signaling pathways and is locally synthesized in the brain by the enzyme aromatase. However, the spatial and temporal dynamics of brain aromatase during AD progression and its relationship to central insulin resistance remain poorly understood. Using the 5xFAD mouse model, we examined whole-brain, regional, and neuron/astrocyte-specific alterations in aromatase expression along disease progression. Whole-brain aromatase expression remained unchanged at 2 months of age but progressively declined at 5 and 9 months, inversely correlating with amyloid-β plaque burden. Regional analysis of the cortex, hippocampal CA1, and hypothalamus revealed progressive aromatase loss in all regions; notably, the hypothalamus exhibited a significant decline at the earliest disease stage examined, preceding comparable changes in the cortex and hippocampus, while an age-related decline cannot be fully excluded, as only a single-aged wild-type (WT) control was used. Cell-level analysis revealed a progressive reduction in neuronal aromatase expression, whereas astrocytic aromatase displayed a biphasic response, increasing during early disease stages before declining at later stages. In parallel, neuronal insulin-resistance signaling increased progressively with disease advancement and was negatively correlated with neuronal aromatase expression across all regions examined (r = −0.82 to −0.87). Collectively, these findings demonstrate progressive regional and neuron/astrocyte-specific alterations in brain aromatase during the progression of amyloid pathology, identifying early hypothalamic vulnerability as a feature of AD-associated altered insulin signaling.