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

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 em...

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Published in:Science (American Association for the Advancement of Science) Vol. 379; no. 6628; p. eadd1236
Main Authors: Seo, Dong-Oh, O'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
Format: Journal Article
Language:English
Published: United States 13.01.2023
Subjects:
Animals
Anti-Bacterial Agents - pharmacology
Apolipoproteins E - genetics
Apolipoproteins E - metabolism
Disease Models, Animal
Gastrointestinal Microbiome - drug effects
Gastrointestinal Microbiome - physiology
Humans
Mice
Mice, Transgenic
Neuroinflammatory Diseases - genetics
Neuroinflammatory Diseases - metabolism
Neuroinflammatory Diseases - microbiology
Sex Factors
tau Proteins - genetics
tau Proteins - metabolism
Tauopathies - genetics
Tauopathies - metabolism
Tauopathies - microbiology
ISSN:1095-9203, 1095-9203
Online Access:Get more information
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Summary: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.
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ISSN:1095-9203
1095-9203
DOI:10.1126/science.add1236