Microbial Sources of Amyloid and Relevance to Amyloidogenesis and AlzheimerÂ’s Disease (AD)

Abstract

Since the inception of the human microbiome project (HMP) by the US National Institutes of Health (NIH) in 2007 there has been a keen resurgence in our recognition of the human microbiome and its contribution to development, immunity, neurophysiology, metabolic and nutritive support to central nervous system (CNS) health and disease. What is not generally appreciated is that (i) the ~1014 microbial cells that comprise the human microbiome outnumber human host cells by approximately one hundred-to-one; (ii) together the microbial genes of the microbiome outnumber human host genes by about one hundred-and-fifty to one; (iii) collectively these microbes constitute the largest ‘diffuse organ system’ in the human body, more metabolically active than the liver; strongly influencing host nutritive-, innate-immune, neuroinflammatory-, neuromodulatory- and neurotransmission-functions; and (iv) that these microbes actively secrete highly complex, immunogenic mixtures of lipopolysaccharide (LPS) and amyloid from their outer membranes into their immediate environment. While secreted LPS and amyloids are generally quite soluble as monomers over time they form into highly insoluble fibrous protein aggregates that are implicated in the progressive degenerative neuropathology of several common, age-related disorders of the human CNS including Alzheimer’s disease (AD). This general commentary-perspective paper will highlight some recent findings on microbial-derived secreted LPS and amyloids and the potential contribution of these neurotoxic and proinflammatory microbial exudates to age-related inflammatory amyloidogenesis and neurodegeneration, with specific reference to AD wherever possible.

Secretory Products of the Human GI Tract Microbiome and Their Potential Impact on Alzheimer's Disease (AD): Detection of Lipopolysaccharide (LPS) in AD Hippocampus

“…LPSs, as characteristic components of the outer leaflet of the outer membrane of Gram-negative bacteria shed into the extracellular space, play key roles in host-pathogen interactions and the innate-immune system (Hill and Lukiw, 2015; Zhao et al, 2015; Maldonado et al, 2016). While LPSs contain large and hypervariable oligosaccharide/polysaccharide regions, the relatively conserved lipid region (lipid A) is the endotoxic and biologically active moiety that is largely responsible for septic shock (Jiang et al, 2016; Maldonado et al, 2016).…”

Influence of Gut Microbiota on Behavior and Its Disturbances

“…A fuller understanding of the human "hologenome," of human microbial ecosystems and their secretory products should provide a deeper insight into their contribution to age-related neurological diseases associated with amyloidogenesis, CNS inflammation and progressive neurodegeneration [120].…”

“…Bacterial representatives of the gut microbiome excrete lipopolysaccharides (LPSs) and amyloids. These products lead to forceful pro-inflammatory and innateimmune effects, activate the system Following enhanced amyloid aggregation, as well secondary degeneration occur, which are typical signs of AD, together with impaired cleansing mechanisms of Aβ peptide [17,120,121]. It has been suggested that diet and specific nutrients could alert the composition of the intestinal microbiota and might influence the production or aggregation of amyloid proteins [29,114,122].…”

Olfaction, among the First Senses to Develop and Decline

“…Based on their ability to form oligomers and fibrils to surround harmful microbial agents, toxic substances and even aberrant cells, the AMPs produced by the OSNs represent the first and only defensive barrier of the CNS against pathogens. Furthermore, beside its endogenous production, Aβ may also have a microbial origin, aggravating the neurodegenerative process [39,241]. The gastrointestinal (GI) compartment represents the principal source of the human microbiome and is tightly connected with the CNS through the GI tract-CNS axis, which interconnects these structures via immune system molecules, cytokines, hormones and nervous signals [39,[242][243][244].…”