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

• 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 The American Association for the Advancement of Science 13.01.2023
• Subjects: Accumulation; Alzheimer's disease; Animal cognition; Animals; Anti-Bacterial Agents - pharmacology; Antibiotics; Apolipoprotein E; Apolipoproteins; Apolipoproteins E - genetics; Apolipoproteins E - metabolism; Atrophy; Brain; Brain damage; Brain injury; Cognitive ability; Death; Disease Models, Animal; Euthanasia; Fatty acids; Females; Gastrointestinal Microbiome - drug effects; Gastrointestinal Microbiome - physiology; Gene expression; Germfree; Glial cells; Head injuries; Health services; Hippocampus; Humans; Immune response; Inflammation; Intestinal microflora; Isoforms; Males; Metabolites; Mice; Mice, Transgenic; Microbiomes; Microbiota; Morphology; Neurodegeneration; Neurodegenerative diseases; Neuroinflammatory Diseases - genetics; Neuroinflammatory Diseases - metabolism; Neuroinflammatory Diseases - microbiology; Neurological Impairments; Pathogenesis; Pathology; Reduction; Risk analysis; Risk factors; Senile plaques; Sex Factors; Statistical Significance; Tau protein; tau Proteins - genetics; tau Proteins - metabolism; Tauopathies - genetics; Tauopathies - metabolism; Tauopathies - microbiology; Transgenic mice; β-Amyloid
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.add1236

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. The accumulation of certain forms of the tau protein in the brain is linked to loss of nerve cells, inflammation, and cognitive decline in Alzheimer’s disease and several other neurodegenerative diseases. Apolipoprotein-E (APOE), the strongest genetic risk factor for Alzheimer’s disease, regulates brain inflammation and tau-mediated brain damage; however, the gut microbiota also regulates brain inflammation. In a mouse model of tau-mediated brain injury, Seo et al . found that manipulation of the gut microbiota resulted in a strong reduction of inflammation, tau pathology, and brain damage in a sex- and APOE-dependent manner (see the Perspective by Jain and Li). —SMH Manipulation of gut microbiota attenuates brain atrophy in a genetically engineered mouse model of tau-mediated neurodegeneration.