Gastrointestinal-tract, microbiome-derived lipopolysaccharide and other pro-inflammatory neurotoxins in sporadic Alzheimer's disease.

Abstract

The human gastrointestinal (GI)-tract contains many thousands of different kinds of microbes that are mostly bacteria and collectively make up the GI-tract microbiome. Studies in Alzheimer's disease (AD) brain, human brain cells and transgenic AD (TgAD) murine models indicate that increased secretion of pro-inflammatory neurotoxins from GI-tract microbes can induce alterations in both GI-tract and blood-brain barrier (BBB) permeability permitting neurotoxins to enter the CNS to contribute to AD-type change. More specifically our lab and others have recently provided evidence of increased enterotoxigenic Bacteroides fragilis lipopolysaccharide (LPS) and B. fragilis-derived metallopeptidase fragilysin presence in AD. GI-tract microbiome culture and analysis; LPS and fragilysin extraction and quality control; culture of Bacteroides fragilis; RNA sequencing; bioinformatics; TgAD murine models (5xFAD); RESULT: LPS disrupts neuronal-function in stressed human neuronal-glial (HNG) cells, in TgAD models and is elevated in the blood and brain of AD patients. Fragilysin damages cell-cell adhesion, alters GI-tract and BBB integrity and like BF-LPS up-regulates the pro-inflammatory transcription factor NF-kB (p50/p65) in brain cells. In turn, NF-kB (p50/p65) induces transcription from a specialized family of pro-inflammatory, NF-kB-transcription-sensitive, neocortex- and hippocampus abundant microRNAs that include miRNA-9, miRNA-125b and miRNA-146a, and these specifically down-regulate AD-relevant target messenger RNAs (mRNAs) known to contribute to AD-type change. These gene targets include down-regulated mRNAs that encode synapsin-2 (SYN-2), the triggering receptor expressed in myeloid/microglia cells (TREM2) and complement factor H (CFH). This paper will update our current understanding of the GI-tract-microbiome-LPS-NF-kB (p50/p65)-microRNA-messenger RNA (miRNA-mRNA) axis in AD and in AD models and how amyloid deposition appears to enhance the overall neuro-toxicity and neuro-inflammatory properties of LPS in human brain neurons.