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Sepsis exacerbates Alzheimer’s disease pathophysiology, modulates the gut microbiome, increases neuroinflammation and amyloid burden

Molecular Psychiatry volume 28, pages 4463–4473 (2023)Cite this article

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A Correction to this article was published on 22 January 2024

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Abstract

While our understanding of the molecular biology of Alzheimer’s disease (AD) has grown, the etiology of the disease, especially the involvement of peripheral infection, remains a challenge. In this study, we hypothesize that peripheral infection represents a risk factor for AD pathology. To test our hypothesis, APP/PS1 mice underwent cecal ligation and puncture (CLP) surgery to develop a polymicrobial infection or non-CLP surgery. Mice were euthanized at 3, 30, and 120 days after surgery to evaluate the inflammatory mediators, glial cell markers, amyloid burden, gut microbiome, gut morphology, and short-chain fatty acids (SCFAs) levels. The novel object recognition (NOR) task was performed 30 and 120 days after the surgery, and sepsis accelerated the cognitive decline in APP/PS1 mice at both time points. At 120 days, the insoluble Aβ increased in the sepsis group, and sepsis modulated the cytokines/chemokines, decreasing the cytokines associated with brain homeostasis IL-10 and IL-13 and increasing the eotaxin known to influence cognitive function. At 120 days, we found an increased density of IBA-1-positive microglia in the vicinity of Aβ dense-core plaques, compared with the control group confirming the predictable clustering of reactive glia around dense-core plaques within 15 μm near Aβ deposits in the brain. In the gut, sepsis negatively modulated the α- and β-diversity indices evaluated by 16S rRNA sequencing, decreased the levels of SCFAs, and significantly affected ileum and colon morphology in CLP mice. Our data suggest that sepsis-induced peripheral infection accelerates cognitive decline and AD pathology in the AD mouse model.

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Fig. 1: Cognitive impairment evaluated by novel object recognition (NOR) task in APP/PS1 mice challenged with CLP.
Fig. 2: Effect of polymicrobial sepsis on the insoluble and soluble fraction of Aβ1-40 and Aβ1-42 in the APP/PS1 mice brain.
Fig. 3: Effect of polymicrobial sepsis on microglial, astroglial activation, and Aβ burden in the APP/PS1 mice PFC and hippocampus.
Fig. 4: Assessment of immune activation by measuring the levels of cytokines and chemokines in the APP/PS1 mice brain after CLP challenge.
Fig. 5: Analysis of gut microbiome profile and the relative abundance of phyla and class level difference after polymicrobial infection as measured in the feces of APP/PS1 mice.
Fig. 6: Cecum feces SCFAs levels and morphometric measurement of intestinal villus length and crypt depth after polymicrobial sepsis in APP/PS1 mice.

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Data availability

The datasets during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

We acknowledge MD Anderson Advanced Microscopy Core Facility, NIH grant (S10RR029552) and Microbiome Insights Inc., Vancouver, Canada (SCFAs analysis), and the infrastructure and support of the Alkek Center for Metagenomics and Microbiome Research – CMMR (16S rRNA sequencing). This work was supported by startup funds from The University of Texas Health Science Center at Houston to RM and TB, Alzheimer’s Association® AARGDNTF-19-619645 and TARCC 2022-24 to TB, NIH/NIA grant 1RF1AG072491 to RM and TB, and FAPESP grant 21/06496-4 to CHRC.

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Authors and Affiliations

  1. Faillace Department of Psychiatry and Behavioural Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA

    Vijayasree V. Giridharan, Carlos Henrique R. Catalão & Tatiana Barichello

  2. Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA

    Celso S. G. Catumbela, Juneyoung Lee, Bhanu P. Ganesh & Rodrigo Morales

  3. Department of Neurosciences and Behavioral Sciences, Ribeirao Preto Medical School, University of Sao Paulo (USP), Ribeirao Preto, SP, Brazil

    Carlos Henrique R. Catalão

  4. Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil

    Fabricia Petronilho, Felipe Dal-Pizzol & Tatiana Barichello

  5. Centro Integrativo de Biología y Química Aplicada (CIBQA), Universidad Bernardo O’Higgins, Santiago, Chile

    Rodrigo Morales

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Contributions

Conception and design of the work, TB, RM, and VVG; acquisition, analysis, interpretation of data, VVG; brain and gut amyloid-beta evaluation, CSGC; gut microbiome analysis, VVG and JL; gut immunofluorescence and analysis, BPG; and have drafted the work TB and VVG; substantively revised the manuscript CHRC, FP, FD, RM, TB and VG.

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Correspondence to Tatiana Barichello.

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The original online version of this article was revised: In this article the wrong figure appeared as Fig. 3F and 3J.; the figure should have appeared as shown below.The original article has been corrected.

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Giridharan, V.V., Catumbela, C.S.G., Catalão, C.H.R. et al. Sepsis exacerbates Alzheimer’s disease pathophysiology, modulates the gut microbiome, increases neuroinflammation and amyloid burden. Mol Psychiatry 28, 4463–4473 (2023). https://doi.org/10.1038/s41380-023-02172-2

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