# Female‐biased astrocytic priming shapes early locus coeruleus vulnerability in an Aβ oligomer milieu

## TL;DR

Female mice show early astrocyte changes in a brain region linked to Alzheimer's disease, which may explain sex differences in disease vulnerability.

## Contribution

This study reveals sex-specific astrocytic priming in the locus coeruleus during early Alzheimer's pathology in mice.

## Key findings

- Females exhibit higher brainstem Aβ42 oligomers and astrocyte-specific MRS signatures.
- Environmental enrichment reverses astrocytic and noradrenergic changes in female APP/PS1 mice.
- Female astrocytes show elevated lactate and oxidative phosphorylation transcripts without morphological changes.

## Abstract

The locus coeruleus (LC) is an early site of Alzheimer's disease (AD) pathology, yet the role of brainstem astrocytes in early, sex‐dependent vulnerability remains unclear.

In 2‐ to 3‐month‐old APP/PS1 mice, we combined in vivo proton magnetic resonance spectroscopy (MRS) of the brainstem with region‐resolved molecular analyses, including quantitative real‐time polymerase chain reaction, amyloid beta 42 (Aβ42) oligomers enzyme‐linked immunosorbent assay, lactate assay, immunohistochemistry, immunoblotting, astrocyte isolation, and 3D structural assessment. Environmental enrichment (EE) served as a non‐pharmacologic intervention.

Females exhibited higher brainstem Aβ42 oligomers and an astrocyte‐weighted MRS profile. Pontine glial fibrillary acidic protein (GFAP), complement component 3, and nuclear factor kappa‐light‐chain‐enhancer of activated B cells were selectively upregulated without pan‐reactive astrocytic and microglial markers. LC‐restricted GFAP elevation occurred without changes in astrocyte counts or morphology, indicating a “primed” state. Females also showed higher lactate levels, increased monocarboxylate transporter 2 expression, and elevations in selected oxidative phosphorylation‐associated transcripts, and reduced astrocytic alpha 2A‐adrenergic receptor expression. EE normalized noradrenergic and pontine astrocytic changes.

Female‐biased, LC‐centric astrocytic priming emerges early in this amyloid‐driven model and is modifiable.

Early astrocytic priming in locus coeruleus (LC) of APP/PS1 mice is stronger in females.Non‐reactive astrocytes show glial fibrillary acidic protein, complement component 3, nuclear factor kappa‐light‐chain‐enhancer of activated B cells upregulation with intact LC neurons.Females show higher glutamine, myo‐inositol, glutathione, and taurine levels.Noradrenergic tuning adapts in males via NET/α2A receptors but is impaired in females.Environmental enrichment restores LC astrocytic state, metabolic profile, and noradrenergic regulation.

Early astrocytic priming in locus coeruleus (LC) of APP/PS1 mice is stronger in females.

Non‐reactive astrocytes show glial fibrillary acidic protein, complement component 3, nuclear factor kappa‐light‐chain‐enhancer of activated B cells upregulation with intact LC neurons.

Females show higher glutamine, myo‐inositol, glutathione, and taurine levels.

Noradrenergic tuning adapts in males via NET/α2A receptors but is impaired in females.

Environmental enrichment restores LC astrocytic state, metabolic profile, and noradrenergic regulation.