ASTROCYTE–NORADRENERGIC INTERACTIONS IN THE LOCUS COERULEUS SHOW SEX-SPECIFIC CHANGES IN EARLY ALZHEIMER’S DISEASE

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by amyloid-β (Aβ) plaque deposition and hyperphosphorylated tau pathology. One of the earliest brain regions affected is the locus coeruleus (LC), a small noradrenergic nucleus located in the pons of the brainstem. The LC is the major source of norepinephrine (NE) in the brain and broadly regulates arousal, circuit function, and neuromodulator–glia interactions. Astrocytes are key targets of NE signalling and play a central role in synaptic maintenance and homeostasis; however, how LC astrocytes respond during early Aβ exposure, and whether this response differs by sex, remains unknown. To address this, we studied 2–3-month-old male and female APPswe/PSEN1dE9 mice at a pre-plaque, Aβ-oligomer-enriched stage. Female mice exhibited higher brainstem Aβ₄₂ oligomer levels and a selective increase in astrocytic GFAP restricted to the LC, while astrocyte number, morphology, and microglial markers were unchanged, indicating molecular astrocytic priming rather than reactive gliosis. Consistent with this primed state, female mice showed elevated levels of complement component 3 (C3), an inflammatory marker, in astrocyte-enriched fractions isolated from the pons that houses LC. Noradrenergic regulation showed sex divergence: males displayed reduced norepinephrine transporter (NET) expression with increased astrocytic α2A-adrenergic receptor (α2AR) levels, whereas females showed preserved NET, reduced astrocytic α2AR, and increased tyrosine hydroxylase expression. Environmental enrichment, used as a non-pharmacological intervention, normalized astrocytic and noradrenergic alterations across sexes. Together, these findings identify LC astrocytes as early, sex-sensitive responders in AD and highlight the LC-astrocyte axis as a modifiable contributor to early disease vulnerability.