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

Autor: Giridharan VV; Faillace Department of Psychiatry and Behavioural Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA., Catumbela CSG; Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA., Catalão CHR; Faillace Department of Psychiatry and Behavioural Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.; Department of Neurosciences and Behavioral Sciences, Ribeirao Preto Medical School, University of Sao Paulo (USP), Ribeirao Preto, SP, Brazil., Lee J; Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA., Ganesh BP; Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA., Petronilho F; Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil., Dal-Pizzol F; Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil., Morales R; Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.; Centro Integrativo de Biología y Química Aplicada (CIBQA), Universidad Bernardo O'Higgins, Santiago, Chile., Barichello T; Faillace Department of Psychiatry and Behavioural Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA. Tatiana.Barichello@uth.tmc.edu.; Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil. Tatiana.Barichello@uth.tmc.edu.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2023 Oct; Vol. 28 (10), pp. 4463-4473. Date of Electronic Publication: 2023 Jul 14.
DOI: 10.1038/s41380-023-02172-2
Abstrakt: 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.
(© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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