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

BACKGROUND: Neuroinflammation, impaired metabolism, and hypoperfusion are fundamental pathological hallmarks of early Alzheimer's 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. METHODS: 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 lipopolysaccharide-induced neuroinflammation. RESULTS: 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. CONCLUSIONS: 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 neuroinflammation's influence on neuroimaging biomarkers for early AD diagnosis.

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

Neuroinflammation, impaired metabolism, and hypoperfusion are fundamental pathological hallmarks of early Alzheimer's 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 neuroinflammation's influence on neuroimaging biomarkers for early AD diagnosis.

Regulation of Metabolic Health by an "Olfactory-Hypothalamic Axis" and Its Possible Implications for the Development of Therapeutic Approaches for Obesity and T2D.

The olfactory system is responsible for the reception, integration and interpretation of odors. However, in the last years, it has been discovered that the olfactory perception of food can rapidly modulate the activity of hypothalamic neurons involved in the regulation of energy balance. Conversely, the hormonal signals derived from changes in the metabolic status of the body can also change the sensitivity of the olfactory system, suggesting that the bidirectional relationship established between the olfactory and the hypothalamic systems is key for the maintenance of metabolic homeostasis. In the first part of this review, we describe the possible mechanisms and anatomical pathways involved in the modulation of energy balance regulated by the olfactory system. Hence, we propose a model to explain its implication in the maintenance of the metabolic homeostasis of the organism. In the second part, we discuss how the olfactory system could be involved in the development of metabolic diseases such as obesity and type two diabetes and, finally, we propose the use of intranasal therapies aimed to regulate and improve the activity of the olfactory system that in turn will be able to control the neuronal activity of hypothalamic centers to prevent or ameliorate metabolic diseases.

Time-restricted feeding prevents depressive-like and anxiety-like behaviors in male rats exposed to an experimental model of shift-work.

Individuals who regularly shift their sleep timing, like night and/or shift-workers suffer from circadian desynchrony and are at risk of developing cardiometabolic diseases and cancer. Also, shift-work is are suggested to be a risk factor for the development of mood disorders such as the burn out syndrome, anxiety, and depression. Experimental and clinical studies provide evidence that food intake restricted to the normal activity phase is a potent synchronizer for the circadian system and can prevent the detrimental health effects associated with circadian disruption. Here, we explored whether adult male Wistar rats exposed to an experimental model of shift-work (W-AL) developed depressive and/or anxiety-like behaviors and whether this was associated with neuroinflammation in brain areas involved with mood regulation. We also tested whether time-restricted feeding (TRF) to the active phase could ameliorate circadian disruption and therefore would prevent depressive and anxiety-like behaviors as well as neuroinflammation. In male Wistar rats, W-AL induced depressive-like behavior characterized by hypoactivity and anhedonia and induced increased anxiety-like behavior in the open field test. This was associated with increased number of glial fibrillary acidic protein and IBA-1-positive cells in the prefrontal cortex and basolateral amygdala. Moreover W-AL caused morphological changes in the microglia in the CA3 area of the hippocampus indicating microglial activation. Importantly, TRF prevented behavioral changes and decreased neuroinflammation markers in the brain. Present results add up evidence about the importance that TRF in synchrony with the light-dark cycle can prevent neuroinflammation leading to healthy mood states in spite of circadian disruptive conditions.

Early Post-stroke Activation of Vascular Endothelial Growth Factor Receptor 2 Hinders the Receptor 1-Dependent Neuroprotection Afforded by the Endogenous Ligand.

Vascular endothelial growth factor (VEGF) has long been connected to the development of tissue lesion following ischemic stroke. Contradictory findings either situate VEGF as a promoter of large infarct volumes or as a potential attenuator of damage due to its well documented neuroprotective capability. The core of this discrepancy mostly lies on the substantial number of pleiotropic functions driven by VEGF. Mechanistically, these effects are activated through several VEGF receptors for which various closely related ligands exist. Here, we tested in an experimental model of stroke how the differential activation of VEGF receptors 1 and 2 would modify functional and histological outcomes in the acute phase post-ischemia. We also assessed whether VEGF-mediated responses would involve the modulation of inflammatory mechanisms and how this trophic factor acted specifically on neuronal receptors. We produced ischemic infarcts in adult rats by transiently occluding the middle cerebral artery and induced the pharmacological inhibition of VEGF receptors by i.c.v. administration of the specific VEGFR2 inhibitor SU1498 and the pan-VEGFR blocker Axitinib. We evaluated the neurological performance of animals at 24 h following stroke and the occurrence of brain infarctions analyzed at the gross metabolic and neuronal viability levels. We also assessed the induction of peripheral pro- and anti-inflammatory cytokines in the cerebrospinal fluid and blood and assessed the polarization of activated microglia. Finally, we studied the direct involvement of cortical neuronal receptors for VEGF with in vitro assays of excitotoxic damage. Preferential VEGFR1 activation by the endogenous ligand promotes neuronal protection and prevents the presentation of large volume infarcts that highly correlate with neurological performance, while the concomitant activation of VEGFR2 reduces this effect, even in the presence of exogenous ligand. This process partially involves the polarization of microglia to the state M2. At the cellular level, neurons also responded better to the preferential activation of VEGFR1 when challenged to N-methyl-D-aspartate-induced excitotoxicity. Endogenous activation of VEGFR2 hinders the neuroprotective mechanisms mediated by the activation of VEGFR1. The selective modulation of these concurrent processes might enable the development of therapeutic approaches that target specific VEGFR1-mediated signaling during the acute phase post-stroke.