Amyloid BETA‐42 peptides facilitate the entry of gastrointestinal tract microbiome‐derived lipopolysaccharide into human neurons

Background Lipopolysaccharide (LPS) derived from the human gastrointestinal (GI)‐tract microbiome: (i) has been recently shown to target, accumulate within, and eventually encapsulate neuronal nuclei of the human central nervous system (CNS) in Alzheimer’s disease (AD) brain; and (ii) recent evidence indicates that this action appears to restrict the outward flow of genetic information from neuronal nuclei. It has previously been shown that in LPS‐encased neuronal nuclei in AD brain there is a specific disruption in the output and expression of two AD‐relevant, neuron‐specific markers encoding the cytoskeletal neurofilament light (NF‐L) chain protein and the synaptic phosphoprotein synapsin‐1 (SYN1) involved in the regulation of neurotransmitter release. The biophysical mechanisms involved in the facilitation of the targeting of LPS to neuronal cells and nuclei, and eventual nuclear envelopment and functional disruption are not entirely clear. Method Isolation of lipopolysaccharide (LPS), bacterial amyloid(s), enterotoxin(s) and small non‐coding RNAs (sncRNAs) from Gram‐negative anaerobic bacilli of the human gastrointestinal (GI) tract; isolation of human temporal lobe neocortical, hippocampal and retinal tissues; aging 5xFAD (amyloid over‐expressing; C57BL6 background); RNA sequencing; LED Northern dot blots; Western analysis, immunocytochemistry; biostatistics, bioinformatics Result In this presentation we will (i) provide novel evidence in human neuronal‐glial (HNG) cells in primary co‐culture that the incubation of LPS with amyloid‐beta 42 (Aβ42) peptides facilitates the association of lipoglycans such as LPS with neuronal cells; and (ii) that a similar phenomenon is observed in the brains of 5xFAD transgenic mice, an amyloid over‐expressing transgenic model of AD as well as in AD‐affected neocortex and hippocampal CA1. Conclusion These novel findings: (i) support a novel pathogenic role for Aβ42 peptides in neurons via the formation of pores across the nuclear membrane and/or a significant biophysical disruption of the neuronal nuclear envelope; and (ii) advance the concept that the Aβ42 peptide‐facilitated entry of LPS into brain neurons, accession of neuronal nuclei, and down‐regulation of neuron‐specific components such as NF‐L and SYN1 may contribute significantly to neuropathological deficits as are characteristically observed in AD‐affected brain.