Microbial modulations using fecal microbiota transplantation improves cerebral amyloidosis, taupathy and gliosis in ADLPAPT transgenic mice.

Cerebral amyloidosis and severe tauopathy in the brain are key pathological features of Alzheimer's disease (AD), resulting in reactive gliosis and behavioral abnormalities of learning and memory. Despite a strong influence of the intestinal microbiota on neurodevelopment and neurological disorders, a functional link between the gut microbiota and AD remains unknown. Using a newly developed ADLPAPT transgenic mouse model that overexpresses human mutant APP/PS1 and mutant tau, we examined the impact of the gut microbiota on AD pathogenesis. The composition of the gut microbiota in ADLPAPT mice differed from that of healthy wild type (WT) mice; these differences appeared in early life of ADLPAPT mice before AD pathogenesis. Also, ADLPAPT mice showed low-grade inflammation, high gut permeability and metabolic endotoxemia. RNA-Seq analysis of colonic tissue revealed that aging-related tissue degeneration and macrophage dysfunction occurred earlier in ADLPAPT mice, compared to WT mice. Interestingly, frequent transfer of fecal microbiota from the WT mice into ADLPAPT mice ameliorated Aß plaque, neurofibrillary tangle formation and glial reactivity, thereby improving learning behavior in recipient mice. In addition, abnormalities in colonic gene expressions were recovered by fecal microbiota transfer. These findings suggest that gut microbial dysbiosis and gut microbiota-derived factors contribute to the development of AD.