Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
Female-biased astrocytic priming shapes early locus coeruleus vulnerability in an Aβ oligomer milieu.
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Kushwaha Srishti, Roy Choudhury Rupsa, Bhat Priyanka, Kumaran S Senthil, Karunakaran Smitha
Аннотация
INTRODUCTION: 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.
METHODS: 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.
RESULTS: 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.
DISCUSSION: Female-biased, LC-centric astrocytic priming emerges early in this amyloid-driven model and is modifiable.
METHODS: 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.
RESULTS: 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.
DISCUSSION: Female-biased, LC-centric astrocytic priming emerges early in this amyloid-driven model and is modifiable.