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Disruptions to the gut-brain-axis have been linked to neurodegenerative disorders. Of these disruptions, reductions in the levels of short-chain fatty acids (SCFAs), like butyrate, have been observed in mouse models of Alzheimer's disease (AD). Butyrate supplementation in mice has shown promise in reducing neuroinflammation, amyloid-β accumulation, and enhancing memory. However, the underlying mechanisms remain unclear. To address this, we investigated the impact of butyrate on energy metabolism in mouse brain slices, primary cultures of astrocytes and neurons and in-vivo by dynamic isotope labelling with [U-13C]butyrate and [1,2-13C]acetate to map metabolism via mass spectrometry. Metabolic competition assays in cerebral cortical slices revealed no competition between butyrate and the ketone body, β-hydroxybutyrate, but competition with acetate. Astrocytes favoured butyrate metabolism compared to neurons, suggesting that the astrocytic compartment is the primary site of butyrate metabolism. In-vivo metabolism investigated in the 5xFAD mouse, an AD pathology model, showed no difference in 13C-labelling of TCA cycle metabolites between wild-type and 5xFAD brains, but butyrate metabolism remained elevated compared to acetate in both groups, indicating sustained uptake and metabolism in 5xFAD mice. Overall, these findings highlight the role of astrocytes in butyrate metabolism and the potential use of butyrate as an alternative brain fuel source. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is characterized by complex interactions between neuropathological markers, metabolic dysregulation, and structural brain changes. In this study, we utilized a multimodal approach, combining immunohistochemistry, functional metabolic mapping, and microstructure sensitive diffusion MRI (dMRI) to progressively investigate these interactions in the 5xFAD mouse model of AD. Our analysis revealed age-dependent and region-specific accumulation of key AD markers, including amyloid-beta (Aβ), GFAP, and IBA1, with significant differences observed between the hippocampal formation and upper and lower regions of the cortex by 6 months of age. Functional metabolic mapping validated localized disruptions in energy metabolism, with glucose hypometabolism in the hippocampus and impaired astrocytic metabolism in the cortex. Notably, increased cortical glutaminolysis suggested a shift in microglial metabolism, reflecting an adaptive response to neuroinflammatory processes. While dMRI showed no significant microstructural differences between 5xFAD and wild-type controls, the study highlights the importance of metabolic alterations as critical events in AD pathology. These findings emphasize the need for targeted therapeutic strategies addressing specific metabolic disturbances and underscore the potential of integrating advanced imaging with metabolic and molecular analyses to advance our understanding of AD progression. [ABSTRACT FROM AUTHOR]

Glutamate recycling between neurons and astrocytes is essential to maintain neurotransmitter homeostasis. Disturbances in glutamate homeostasis, resulting in excitotoxicity and neuronal death, have been described as a potential mechanism in Alzheimer's disease (AD) pathophysiology. However, glutamate neurotransmitter metabolism in different human brain cells, particularly astrocytes, has been poorly investigated at the early stages of AD. We sought to investigate glucose and glutamate metabolism in AD by employing human induced pluripotent stem cell (hiPSC)-derived astrocytes and neurons carrying mutations in the amyloid precursor protein (APP) or presenilin-1 (PSEN-1) gene as found in familial types of AD (fAD). Methods such as livecell bioenergetics and metabolic mapping using [13C]-enriched substrates were used to examine metabolism in the early stages of AD. Our results revealed greater glycolysis and glucose oxidative metabolism in astrocytes and neurons with APP or PSEN-1 mutations, accompanied by an elevated glutamate synthesis compared to control WT cells. Astrocytes with APP or PSEN-1 mutations exhibited reduced expression of the excitatory amino acid transporter 2 (EAAT2), and glutamine uptake increased in mutated neurons, with enhanced glutamate release specifically in neurons with a PSEN-1 mutation. These results demonstrate a hypermetabolic phenotype in astrocytes with fAD mutations possibly linked to toxic glutamate accumulation. Our findings further identify metabolic imbalances that may occur in the early phases of AD pathophysiology. [ABSTRACT FROM AUTHOR]