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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\u2019s 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\u2013brain barrier into the brain, a pathological process that increases during aging and in vascular disorders, including \u2018leaky gut syndrome\u2019. 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\u2013NF-kB\u2013miRNA-30b\u2013NF-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.<\/jats:p>","DOI":"10.3390\/ijms232012671","type":"journal-article","created":{"date-parts":[[2022,10,24]],"date-time":"2022-10-24T04:40:36Z","timestamp":1666586436000},"page":"12671","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["Lipopolysaccharides (LPSs) as Potent Neurotoxic Glycolipids in Alzheimer\u2019s Disease (AD)"],"prefix":"10.3390","volume":"23","author":[{"given":"Yuhai","family":"Zhao","sequence":"first","affiliation":[{"name":"LSU Neuroscience Center, Louisiana State University Health Science Center, New Orleans, LA 70112, USA"},{"name":"Department of Cell Biology and Anatomy, LSU Health Science Center, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian R.","family":"Jaber","sequence":"additional","affiliation":[{"name":"LSU Neuroscience Center, Louisiana State University Health Science Center, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aileen I.","family":"Pogue","sequence":"additional","affiliation":[{"name":"Alchem Biotech Research, Toronto, ON M5S 1A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan M.","family":"Sharfman","sequence":"additional","affiliation":[{"name":"LSU Neuroscience Center, Louisiana State University Health Science Center, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Taylor","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology & Parasitology, LSU Health Science Center, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter J.","family":"Lukiw","sequence":"additional","affiliation":[{"name":"LSU Neuroscience Center, Louisiana State University Health Science Center, New Orleans, LA 70112, USA"},{"name":"Alchem Biotech Research, Toronto, ON M5S 1A8, Canada"},{"name":"Department of Ophthalmology, LSU Health Science Center, New Orleans, LA 70112, USA"},{"name":"Department Neurology, Louisiana State University Health Science Center, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1136\/gutjnl-2015-309990","article-title":"The gut microbiota and host health: A new clinical frontier","volume":"65","author":"Marchesi","year":"2016","journal-title":"Gut"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Bhatia, N.Y., Jalgaonkar, M.P., Hargude, A.B., Sherje, A.P., Oza, M., and Doshi, G.M. 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