Lipopolysaccharides (LPSs) as Potent Neurotoxic Glycolipids in Alzheimer’s Disease (AD)

Abstract

Lipopolysaccharides (LPSs) are microbiome-derived glycolipids that are among the most potent pro-inflammatory neurotoxins known. In Homo sapiens, the major sources of LPSs are gastrointestinal (GI)-tract-resident facultative anaerobic Gram-negative bacilli, including Bacteroides fragilis and Escherichia coli. LPSs have been abundantly detected in aged human brain by multiple independent research investigators, and an increased abundance of LPSs around and within Alzheimer’s disease (AD)-affected neurons has been found. Microbiome-generated LPSs and other endotoxins cross GI-tract biophysiological barriers into the systemic circulation and across the blood–brain barrier into the brain, a pathological process that increases during aging and in vascular disorders, including ‘leaky gut syndrome’. Further evidence indicates that LPSs up-regulate pro-inflammatory transcription factor complex NF-kB (p50/p65) and subsequently a set of NF-kB-sensitive microRNAs, including miRNA-30b, miRNA-34a, miRNA-146a and miRNA-155. These up-regulated miRNAs in turn down-regulate a family of neurodegeneration-associated messenger RNA (mRNA) targets, including the mRNA encoding the neuron-specific neurofilament light (NF-L) chain protein. While NF-L has been reported to be up-regulated in peripheral biofluids in AD and other progressive and lethal pro-inflammatory neurodegenerative disorders, NF-L is significantly down-regulated within neocortical neurons, and this may account for neuronal atrophy, loss of axonal caliber and alterations in neuronal cell shape, modified synaptic architecture and network deficits in neuronal signaling capacity. This paper reviews and reveals the most current findings on the neurotoxic aspects of LPSs and how these pro-inflammatory glycolipids contribute to the biological mechanism of progressive, age-related and ultimately lethal neurodegenerative disorders. This recently discovered gut-microbiota-derived LPS–NF-kB–miRNA-30b–NF-L pathological signaling network: (i) underscores a direct positive pathological link between the LPSs of GI-tract microbes and the inflammatory neuropathology, disordered cytoskeleton, and disrupted synaptic-signaling of the AD brain and stressed human brain cells in primary culture; and (ii) is the first example of a microbiome-derived neurotoxic glycolipid having significant detrimental miRNA-mediated actions on the expression of NF-L, an abundant filamentous protein known to be important in the maintenance of neuronal and synaptic homeostasis.

Epigallocatechin-3-gallate protects bovine ruminal epithelial cells against lipopolysaccharide-induced inflammatory damage by activating autophagy

“…As such, it was essential to outline the major mechanism whereby LPS triggered in ammation in BREC before we could elucidate if EGCG participated in such pathway. The increased phosphorylation of IκBα and NF-κB p65 along with the translocation of NF-κB p65 to the nucleus in response to LPS con rmed that this molecule works through the canonical NF-κB pathway [39]. Thus, the negative effect of EGCG (in a dose-dependent manner) on the mRNA abundance of TLR4 signaling components, phosphorylation of IκBα, NF-κB p65, NLRP3 and caspase-1 protein abundance con rmed that EGCG elicit an anti-in ammatory response by preventing activation of the NF-κB pathway and NLRP3 in ammasome in ruminal epithelial cells.…”

Acupuncture treatment for post-stroke depression: Intestinal microbiota and its role

“…Moreover, as a consequence of stroke, the structural integrity of the BBB is affected and under inflammatory conditions, matrix metalloproteinases (MMPs) can degrade basal layer proteins, increasing the BBB’s permeability ( Zlokovic, 2006 ; Lakhan et al, 2013 ). LPS, SCFAs, adiponectin, vasoactive intestinal peptide (VIP), and some neurotransmitter precursors (e.g., 5-HTP) were more readily transported across the BBB to the brain due to increased BBB permeability ( Birdsall, 1998 ; Dogrukol-Ak et al, 2003 ; Nedorubov et al, 2019 ; Megur et al, 2020 ; Formolo et al, 2022 ; Zhao et al, 2022 ).…”

ApoE Mimetic Peptides to Improve the Vicious Cycle of Malnutrition and Enteric Infections by Targeting the Intestinal and Blood-Brain Barriers

“…Recently, studies have suggested that dysregulation of the gut microbiome can cause neuroinflammatory disturbances in the CNS that are associated with the progression of neurodegenerative diseases, cognitive impairment, and dementia [73]. Aging, malnutrition, and life in adverse environments can alter the gut microbial profile, which is responsible for increasing the secretion of LPSs and abnormal amyloid proteins aggravating the pathogenesis of Alzheimer's disease (AD) and others [74,75]. The disruption of the blood-brain barrier (BBB) and increased permeability of the compromised gastrointestinal tract facilitate the crossing of LPS and abnormal amyloids that may reach the CNS via the oronasal cavity [76].…”