Lipopolysaccharides (LPSs) as Potent Neurotoxic Glycolipids in Alzheimer’s Disease (AD)
Lipopolysaccharides (LPSs) are microbiome-derived glycolipids that are among the most potent pro-inflammatory neurotoxins known. In <i>Homo sapiens</i>, the major sources of LPSs are gastrointestinal (GI)-tract-resident facultative anaerobic Gram-negative bacilli, including <i>Bact...
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MDPI AG
2022-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/20/12671 |
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| author | Yuhai Zhao Vivian R. Jaber Aileen I. Pogue Nathan M. Sharfman Christopher Taylor Walter J. Lukiw |
| author_facet | Yuhai Zhao Vivian R. Jaber Aileen I. Pogue Nathan M. Sharfman Christopher Taylor Walter J. Lukiw |
| author_sort | Yuhai Zhao |
| collection | DOAJ |
| description | Lipopolysaccharides (LPSs) are microbiome-derived glycolipids that are among the most potent pro-inflammatory neurotoxins known. In <i>Homo sapiens</i>, the major sources of LPSs are gastrointestinal (GI)-tract-resident facultative anaerobic Gram-negative bacilli, including <i>Bacteroides fragilis</i> and <i>Escherichia coli</i>. 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: <b>(i)</b> 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 <b>(ii)</b> 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. |
| first_indexed | 2024-03-09T20:04:32Z |
| format | Article |
| id | doaj.art-1ec3987dc81f4f1ab90e3a5fa6f4cb7d |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T20:04:32Z |
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| spelling | doaj.art-1ec3987dc81f4f1ab90e3a5fa6f4cb7d2023-11-24T00:35:10ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-10-0123201267110.3390/ijms232012671Lipopolysaccharides (LPSs) as Potent Neurotoxic Glycolipids in Alzheimer’s Disease (AD)Yuhai Zhao0Vivian R. Jaber1Aileen I. Pogue2Nathan M. Sharfman3Christopher Taylor4Walter J. Lukiw5LSU Neuroscience Center, Louisiana State University Health Science Center, New Orleans, LA 70112, USALSU Neuroscience Center, Louisiana State University Health Science Center, New Orleans, LA 70112, USAAlchem Biotech Research, Toronto, ON M5S 1A8, CanadaLSU Neuroscience Center, Louisiana State University Health Science Center, New Orleans, LA 70112, USADepartment of Microbiology, Immunology & Parasitology, LSU Health Science Center, New Orleans, LA 70112, USALSU Neuroscience Center, Louisiana State University Health Science Center, New Orleans, LA 70112, USALipopolysaccharides (LPSs) are microbiome-derived glycolipids that are among the most potent pro-inflammatory neurotoxins known. In <i>Homo sapiens</i>, the major sources of LPSs are gastrointestinal (GI)-tract-resident facultative anaerobic Gram-negative bacilli, including <i>Bacteroides fragilis</i> and <i>Escherichia coli</i>. 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: <b>(i)</b> 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 <b>(ii)</b> 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.https://www.mdpi.com/1422-0067/23/20/12671Alzheimer’s disease (AD)dysbiosisgastrointestinal tractlipopolysaccharide (LPS)microbiomemiRNA-30 |
| spellingShingle | Yuhai Zhao Vivian R. Jaber Aileen I. Pogue Nathan M. Sharfman Christopher Taylor Walter J. Lukiw Lipopolysaccharides (LPSs) as Potent Neurotoxic Glycolipids in Alzheimer’s Disease (AD) International Journal of Molecular Sciences Alzheimer’s disease (AD) dysbiosis gastrointestinal tract lipopolysaccharide (LPS) microbiome miRNA-30 |
| title | Lipopolysaccharides (LPSs) as Potent Neurotoxic Glycolipids in Alzheimer’s Disease (AD) |
| title_full | Lipopolysaccharides (LPSs) as Potent Neurotoxic Glycolipids in Alzheimer’s Disease (AD) |
| title_fullStr | Lipopolysaccharides (LPSs) as Potent Neurotoxic Glycolipids in Alzheimer’s Disease (AD) |
| title_full_unstemmed | Lipopolysaccharides (LPSs) as Potent Neurotoxic Glycolipids in Alzheimer’s Disease (AD) |
| title_short | Lipopolysaccharides (LPSs) as Potent Neurotoxic Glycolipids in Alzheimer’s Disease (AD) |
| title_sort | lipopolysaccharides lpss as potent neurotoxic glycolipids in alzheimer s disease ad |
| topic | Alzheimer’s disease (AD) dysbiosis gastrointestinal tract lipopolysaccharide (LPS) microbiome miRNA-30 |
| url | https://www.mdpi.com/1422-0067/23/20/12671 |
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