ApoE isoform and microbiota-dependent progression of tau-mediated neurodegeneration

Tau-mediated neurodegeneration (TN) is a hallmark of Alzheimer's disease. Primary tauopathies are characterized by pathological tau accumulation and neuronal and synaptic loss. Studies have shown that ApoE-mediated neuroinflammation is involved in progression of TN and emerging evidence suggests that the gut microbiota regulates neuroinflammation in an APOE-genotype dependent manner. However, there is no evidence showing a causal link of the microbiota to TN. Therefore, we have 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 these manipulations produced a striking reduction of 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 TN.