Cardenas-Rivera, A. | bioRxiv Science

bioRxiv2025

Systemic inflammation reduces astrocyte Ca2+ and neurovascular coupling in a mouse model of Alzheimers disease

Chronic neuroinflammation in Alzheimers disease (AD) activates astrocytes--key regulators of both brain immunity and neurovascular coupling. The primed immune environment in AD brain also renders it highly susceptible to secondary systemic inflammatory challenges. Inflammatory activation drives phenotypic shifts in astrocytes that may compromise their ability to regulate cerebral blood flow. The capacity for inflammation-activated astrocytes to retain this regulatory function, however, remains unknown. To investigate astrocyte regulation of cerebral blood flow in AD brain and under systemic inflammation, we investigated astrocytic Ca2+ dynamics and functional hyperemia at rest and during brief and prolonged sensory stimulation in 12-month-old female APP/PS1dE9 mice. We further examined how a secondary systemic inflammatory challenge induced by low-dose, repeated injection of LPS modulates astrocytic signaling and neurovascular function. AD mice exhibited elevated spontaneous but diminished stimulation-evoked astrocytic Ca2+ activity, accompanied by impaired sustained functional hyperemia, particularly within the capillary network. LPS-induced systemic inflammation further suppressed both spontaneous and evoked astrocytic Ca2+ responses and attenuated functional hyperemia. Together, these findings reveal that inflammation disrupts astrocyte-dependent regulation of sustained neurovascular responses in the AD brain. HIGHLIGHTSO_LIAstrocytes in AD mice exhibit increased spontaneous Ca2+ signaling but cannot sustain stimulus-evoked Ca2+ release. C_LIO_LIReduced astrocyte Ca2+ release during 30s functional brain activation correlates with impaired neurovascular coupling in both penetrating arterioles and capillaries of AD mice C_LIO_LIA secondary, 14-day systemic inflammatory challenge further suppressed functional hyperemia of 30 s stimulus-evoked astrocytic Ca2+ release in AD mice. C_LIO_LIA secondary inflammatory insult lasting 14 days reduced amyloid deposition in the AD brain. C_LI

bioengineering↗

bioRxiv2023

Neuroinflammation increases oxygen extraction in a mouse model of Alzheimer's disease

Neuroinflammation, impaired metabolism, and hypoperfusion are fundamental pathological hallmarks of early Alzheimers disease (AD). Numerous studies have asserted a close association between neuroinflammation and disrupted cerebral energetics. During AD progression and other neurodegenerative disorders, a persistent state of chronic neuroinflammation reportedly exacerbates cytotoxicity and potentiates neuronal death. Here, we assessed the impact of a neuroinflammatory challenge on metabolic demand and microvascular hemodynamics in the somatosensory cortex of an AD mouse model. We utilized in vivo 2-photon microscopy and the phosphorescent oxygen sensor Oxyphor 2P to measure partial pressure of oxygen (pO2) and capillary red blood cell flux in cortical microvessels of awake mice. Intravascular pO2 and capillary RBC flux measurements were performed in 8-month-old APPswe/PS1dE9 mice and wildtype littermates on days 0, 7, and 14 of a 14-day period of lipopolysaccaride-induced neuroinflammation. Before the induced inflammatory challenge, AD mice demonstrated reduced metabolic demand but similar capillary red blood cell flux as their wild type counterparts. Neuroinflammation provoked significant reductions in cerebral intravascular oxygen levels and elevated oxygen extraction in both animal groups, without significantly altering red blood cell flux in capillaries. This study provides evidence that neuroinflammation alters cerebral oxygen demand at the early stages of AD without substantially altering vascular oxygen supply. The results will guide our understanding of neuroinflammations influence on neuroimaging biomarkers for early AD diagnosis.

bioengineering↗