BRAINSTEM ASTROCYTIC METABOLIC ALTERATIONS UNDERLYING SEX-SPECIFIC LOCUS COERULEUS VULNERABILITY IN ALZHEIMER’S DISEASE

Alzheimer’s disease (AD) is a highly prevalent neurodegenerative disorder worldwide, with a greater burden in females. Neuropathological studies demonstrate early tau pathology in neuromodulatory brainstem nuclei, especially the locus coeruleus (LC), which is affected at Braak stage 0. Nevertheless, the mechanisms driving selective LC vulnerability in a sex-specific context remain unclear. We used 2-3-month-old APPswe/PS1dE9 (APP/PS1) mice, a familial, amyloidogenic model of AD and performed brainstem metabolic profiling using in vivo ¹H-magnetic resonance spectroscopy (MRS) on a 7 Tesla MRI system. Further, region-resolved molecular analyses included Aβ42 oligomer ELISA, quantitative real-time PCR, immunohistochemistry, and lactate assays. Post-weaning environmental enrichment (EE) was performed as a non-pharmacological intervention. We observed female APP/PS1 mice exhibited significantly higher brainstem Aβ42 oligomer concentrations compared to males. MRS revealed selective alterations in astrocyte-associated metabolites, including glutamine, glutathione, myo-inositol, and taurine. Quantitative PCR showed increased expression of GFAP, Complement component 3, and NFκB2 in the pons, but not midbrain, with no changes in pan-reactive astrocytic or microglial markers. Female APP/PS1 also displayed elevated lactate levels, increased monocarboxylate transporter 2 expression, and upregulation of oxidative phosphorylation–related transcripts in the pons. Comparative analysis of the pons–LC and midbrain–substantia nigra regions showed selectively elevated GFAP expression in the LC, revealing an astrocytic primed state. EE normalized astrocyte-associated inflammatory markers, reduced LC GFAP expression, and restored oxidative phosphorylation transcripts toward baseline. These findings suggest that a region-specific, early astrocytic primed state in the pons contributes to sex-specific LC vulnerability in AD and can be modulated by EE.