Microbiome-mediated upregulation of microRNA-146a in sporadic Alzheimer's disease

Abstract

The first indication of a potential mechanistic link between the pathobiology of the human gastrointestinal (GI)-tract microbiome and its contribution to the pathogenetic mechanisms of sporadic Alzheimer's disease (AD) came a scant 4 years ago (1). Ongoing research continues to strengthen the hypothesis that neurotoxic microbial-derived components of the GI tract microbiome can cross aging GI tract and blood-brain barriers and contribute to progressive proinflammatory neurodegeneration, as exemplified by the AD-process. Of central interest in these recent investigations are the pathological roles played by human GI tract resident Gram-negative anaerobic bacteria and neurotropic viruses-two prominent divisions of GI tract microbiome-derived microbiota-which harbor considerable pathogenic potential. It is noteworthy that the first two well-studied microbiota-the GI tract abundant Gram-negative bacteria Bacteroides fragilis and the neurotropic herpes simplex virus-1 both share a final common pathway of NF-κB (p50/p65) activation and microRNA-146a induction with ensuing pathogenic stimulation of innate-immune and neuroinflammatory pathways. These appear to strongly contribute to the inflammation-mediated amyloidogenic neuropathology of AD. This communication: (i) will review recent research contributions that have expanded our understanding of the nature of the translocation of microbiome-derived neurotoxins-across biophysiological barriers; (ii) will assess multiple-recent investigations of the induction of the proinflammatory pathogenic microRNA-146a by these two prominent classes of human microbiota; and (iii) will discuss the role of molecular neurobiology and mechanistic contribution of polymicrobial infections to AD-type neuropathological change.