Prolonged systemic inflammation worsens impairments to astrocyte Ca2+ and functional hyperemia in Alzheimer's disease.

INTRODUCTION

Chronic neuroinflammation in Alzheimer's disease (AD) alters astrocyte physiology and neurovascular unit function. AD patients frequently experience recurrent systemic inflammatory insults from comorbid conditions, which act as "secondary-hits" believed to worsen cognitive decline. The impact of these secondary insults  on astrocyte-mediated neurovascular regulation remains unknown.

METHODS

We applied intravital two-photon microscopy to longitudinally investigate astrocytic Ca2 + dynamics and functional hyperemia during sensory stimulation in APP/PS1dE9 mice before and during secondary lipopolysaccharide (LPS)-induced systemic inflammation.

RESULTS

AD mice exhibited diminished stimulation-evoked astrocytic Ca2 + activity, while functional hyperemia remained largely preserved. LPS further suppressed astrocytic Ca2 + responses and produced temporally specific vascular alterations, with AD and wild-type mice following divergent inflammatory trajectories.

DISCUSSION: Our findings provide the first in vivo longitudinal characterization of how secondary systemic inflammation disrupts astrocyte-mediated neurovascular regulation. The selective vulnerability of astrocytic Ca2 + signaling relative to vascular output implicates recurrent inflammatory insults as a clinically relevant contributor to neurovascular dysfunction in preclinical AD.