Absence of a gut microbiota may substantially slow the progression of Alzheimer’s disease-like pathology in mice

Despite previous research indicating the role of gut microbiota in Alzheimer’s disease (AD), the involved mechanisms have not been adequately addressed in model systems. Anecdotal evidence suggests that amyloid plaque formation in amyloid precursor protein transgenic mice differs among mouse facilities with different specific-pathogen-free conditions, leading some to wonder whether the gut microbiota (as shaped by environment) influences these amyloid plaques.

A new study, led by Dr. Tristan Bolmont from the Institute of Microengineering at the Ecole Polytechnique Fédérale de Lausanne and Stemedica International (Switzerland), has found that the gut microbiota may be involved in progression of cerebral Abeta amyloidosis in mice, and thus the mouse mechanisms may possibly applying to the development of AD.

Cerebral deposition of Ab peptides into extracellular amyloid plaques is a critical event in AD development. When studying the fecal microbiota composition of amyloid-b (Ab) precursor protein (APP) transgenic mice (a conventionally-raised mouse model of AD),  the researchers found that it exhibited a shift as compared to non-transgenic wild-type mice. There was an increased abundance of unclassified genera in Rikenellaceae and an unclassified genus in S24-7, whereas Allobaculum and Akkermansia were decreased as compared to conventional wild-type mice. In addition, the relative abundance of several bacterial genera was correlated with levels of Ab in the brain.

The researchers next generated a germ-free (GF) mouse model of cerebral b-amyloidosis to further study the relationship between the gut microbiota and cerebral b-amyloidosis. GF APP transgenic mice exhibited a significant reduction of Ab levels in the brain and blood when compared to control mice colonized with gut microbiota, which it could be explained, at least in part, by reported increased levels of Ab-degrading enzymes in GF APP mice. The reduction of Ab deposition in the brains of GF APP mice was also accompanied by a decrease in cortical neuroinflammation, as evaluated by a decrease in Iba-1-a microglia and macrophage marker-as well as positive immunostaining and decreased levels of T cell-associated cytokines, interferon-gamma (IFN-g), interleukin-2 (IL-2) and IL-5.

Besides this, GF APP transgenic mice colonized with gut microbiota from conventionally-raised APP transgenic mice had an increased cerebral Ab pathology, while colonization with gut microbiota from wild-type mice was less effective in increasing cerebral Ab levels.

In conclusion, these pre-clinical data suggest that gut microbiota is involved in the development of Ab amyloid pathology, thus potentially contributing to the development of neurodegenerative diseases. Further and clinical studies are needed to demonstrate the role of gut microbiota in AD pathology in humans.

Reference:

Harach T, Marungruang N, Duthilleul N, et al. Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota. Sci Rep. 2017; 7:41802. doi: 10.1038/srep41802.