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Amyloid-β driven Alzheimer’s disease reshapes the colonic immune system in mice.

ABSTRACT: The “gut-brain axis” is an emerging target in Alzheimer’s disease (AD), though its immunological features remain poorly understood. Using single-cell RNA sequencing, coupled to extensive spectral-tuning flow cytometry validation of the colon immune compartment in the 5XFAD amyloid-β mouse model, we found several AD-associated changes including in B/plasma cell activity. Notably, levels of CXCR4+ antibody-secreting cells are reduced in 5XFAD colons. This change corresponds with accumulating CXCR4+ B cells and gut-specific IgA+ cells in the brain and dura mater, respectively. Consistently, a chemokine ligand for CXCR4, CXCL12, is expressed at higher levels in the 5XFAD brain and in in silico analyzed human AD brain studies, supporting altered neuroimmune trafficking. An inulin prebiotic fiber diet could expand gut IgA+ cells, rescue peripheral Treg levels, reduce dysbiosis, improve serum microbial metabolite levels and attenuate overall AD-associated frailty. Our study reveals key aspects of the gut-brain axis and highlights potential targets against AD.

ORGANISM(S): mouse gut metagenome

PROVIDER: GSE305697 | GEO | 2025/09/10

REPOSITORIES: GEO

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Project description:Alzheimer’s disease (AD) is an unremitting neurodegenerative disorder characterized by cerebral amyloid-β (Aβ) accumulation and gradual decline in cognitive function. Changes in brain energy metabolism arise in the preclinical phase of AD, suggesting an important metabolic component of early AD pathology. Neurons and astrocytes function in close metabolic collaboration, which is essential for the recycling of neurotransmitters in the synapse. However, how this metabolic interplay may be affected during the early stages of AD development has not been sufficiently investigated. Here, we provide an integrative analysis of cellular metabolism during the early stages of Aβ accumulation in the cerebral cortex and hippocampus of the 5xFAD mouse model of AD. Our electrophysiological examination revealed an increase in spontaneous excitatory signaling in hippocampal brain slices of 5xFAD mice. This hyperactive neuronal phenotype coincided with decreased hippocampal TCA cycle metabolism mapped by stable 13C isotope tracing. Particularly, reduced astrocyte TCA cycle activity led to decreased glutamine synthesis, in turn hampering neuronal GABA synthesis in the 5xFAD hippocampus. In contrast, cerebral cortical slices of 5xFAD mice displayed an elevated capacity for oxidative glucose metabolism suggesting a metabolic compensation. When we explored the brain proteome and metabolome of the 5xFAD mice, we found limited changes, supporting that the functional metabolic disturbances between neurons and astrocytes are early events in AD pathology. In addition, we show that synaptic mitochondrial and glycolytic function was impaired selectively in the 5xFAD hippocampus, whereas non-synaptic mitochondrial function was maintained. These findings were supported by ultrastructural analyses demonstrating disruptions in mitochondrial morphology, particularly in the 5xFAD hippocampus. Collectively, our study reveals complex region and cell specific metabolic adaptations, in the early stages of amyloid pathology, which may be fundamental for the progressing synaptic dysfunction in AD.

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Amyloid-β driven Alzheimer’s disease reshapes the colonic immune system in mice.

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