ApoE isoform- and microbiota-dependent progression of neurodegeneration in a mouse model of tauopathy

• 成果类型: Article
• 署名作者: Seo, Dong-oh; 'Donnell, David; Jain, Nimansha; Ulrich, Jason D.; Herz, Jasmin; Li, Yuhao; Lemieux, Mackenzie; Cheng, Jiye; Hu, Hao; Serrano, Javier R.; Bao, Xin; Franke, Emily; Karlsson, Maria; Meier, Martin; Deng, Su; Desai, Chandani; Dodiya, Hemraj; Lelwala-Guruge, Janaki; Handley, Scott A.; Kipnis, Jonathan; Sisodia, Sangram S.; Gordon, Jeffrey I.; Holtzman, David M.
• 署名单位: Washington University (WUSTL); Washington University (WUSTL); Washington University (WUSTL); Washington University (WUSTL); Washington University (WUSTL); University of Chicago; Washington University (WUSTL)
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-10496
• DOI: 10.1126/science.add1236
• 发表日期: 2023-01-12
• 页码: 155-+
• 关键词: microglia

摘要

Tau-mediated neurodegeneration is a hallmark of Alzheimer's disease. Primary tauopathies are characterized by pathological tau accumulation and neuronal and synaptic loss. Apolipoprotein E (ApoE)-mediated neuroinflammation is involved in the progression of tau-mediated neurodegeneration, and emerging evidence suggests that the gut microbiota regulates neuroinflammation in an APOE genotype-dependent manner. However, evidence of a causal link between the microbiota and tau -mediated neurodegeneration is lacking. In this study, we characterized a genetically engineered mouse model of tauopathy expressing human ApoE isoforms reared under germ-free conditions or after perturbation of their gut microbiota with antibiotics. Both of these manipulations reduced gliosis, tau pathology, and neurodegeneration in a sex-and ApoE isoform-dependent manner. The findings reveal mechanistic and translationally relevant interrelationships between the microbiota, neuroinflammation, and tau-mediated neurodegeneration.