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

Autor(es)

Giridharan, Vijayasree V. ; Catumbela, Celso S. G. ; Catalao, Carlos Henrique R. ; Lee, Juneyoung ; Ganesh, Bhanu P. ; Petronilho, Fabricia ; Dal-Pizzol, Felipe ; Morales, Rodrigo ; Barichello, Tatiana

• Tipo de documento: Artigo Científico
• Fonte: MOLECULAR PSYCHIATRY; v. N/A, p. 11-pg., 2023-07-14.

Resumo

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 A & beta; 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 A & beta; dense-core plaques, compared with the control group confirming the predictable clustering of reactive glia around dense-core plaques within 15 & mu;m near A & beta; deposits in the brain. In the gut, sepsis negatively modulated the & alpha;- and & beta;-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. (AU)

• Processo FAPESP: 21/06496-4 - Inflamação sistêmica mediada por sepse promove patologia da Doença de Alzheimer em modelos animais
• Beneficiário: Carlos Henrique Rocha Catalão
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado