Prolonged β-adrenergic stimulation reduces β2-adrenergic receptor levels and limits astrocytic responsiveness during early amyloid pathology.

Early Alzheimer's disease (AD) is associated with declining noradrenergic tone and early alterations in astrocytic regulation. β-adrenergic signaling links norepinephrine activity to extracellular signal-regulated kinase (ERK) activation and astrocytic responses, but the effects of sustained adrenergic stimulation during early amyloid exposure remain unclear. In this study, wild-type (WT) and pre-plaque APPSwe/PSEN1dE9 (APP/PS1) mice received chronic oral isoproterenol (ISO) from postnatal day 26-47. Hippocampal adrenergic signaling and astrocytic responses were examined at 3 months of age. ISO exposure was associated with reduced β2-adrenergic receptor (β2AR) protein levels and increased β-arrestin-1 expression, consistent with receptor desensitization-associated signaling changes, while ERK phosphorylation remained detectable in both genotypes. WT mice showed increased glial fibrillary acidic protein (GFAP) expression, whereas APP/PS1 mice displayed attenuated molecular responses despite comparable ERK activation. Morphometric analysis revealed no clear evidence of robust astrocytic structural changes at the animal level. These findings indicate that sustained β-adrenergic stimulation is associated with reduced β2AR levels while downstream ERK signaling persists, suggesting that astrocytic responsiveness to adrenergic signaling may be constrained during early amyloid pathology.