The gut microbiome and Alzheimer’s disease: Complex and bidirectional interactions

Tarawneh, Rawan; Penhos, Elena

doi:10.1016/j.neubiorev.2022.104814

Cited by 31 publications

(25 citation statements)

References 349 publications

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“…The gut microbiome and gut permeability are at the cutting edge of research in a growing body of diverse medical conditions. 9 , 10 Gut microbiome/permeability is intimately linked to melatonergic pathway regulation, including by the gut microbiome-derived short-chain fatty acid, butyrate. Butyrate is an epigenetic regulator and histone deacetylase inhibitor (HDACi), with HDACs detrimentally regulating dementias by modifying gene promotors, thereby upregulating YY1-driven transcriptions.…”

Section: Gut Microbiome and Gut Permeability In Modulation Of The Mel...mentioning

confidence: 99%

Why do anti-amyloid beta antibodies not work? Time to reconceptualize dementia pathophysiology by incorporating astrocyte melatonergic pathway desynchronization from amyloid-beta production

Anderson¹

2023

Brazilian Journal of Psychiatry

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Section: Gut Microbiome and Gut Permeability In Modulation Of The Mel...mentioning

confidence: 99%

Why do anti-amyloid beta antibodies not work? Time to reconceptualize dementia pathophysiology by incorporating astrocyte melatonergic pathway desynchronization from amyloid-beta production

Anderson¹

2023

Brazilian Journal of Psychiatry

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“…One major characterized pathogenic role of LPSs appears to be the stimulation of cytokine-, chemokine- and/or ROS-mediated pathological signaling programs that drive the induction of pro-inflammatory transcription factor NF-kB (p50/p65), which subsequently promotes the transcriptional up-regulation of NF-kB-sensitive microRNAs. These, in turn, target AD- or related-disease-associated mRNAs, which ultimately down-regulate critically pathologically relevant gene expression programs, resulting in the initiation, development and/or propagation of human disease [ 21 , 29 , 34 , 49 , 50 , 56 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 72 , 73 , 74 , 75 ]. For example, the LPS-mediated, ROS- and NF-kB-regulated up-regulation of microRNAs miRNA-30b, miRNA-146a and miRNA-155 in transgenic murine models of AD and in AD are now known to target and down-regulate the expression of important neuron-specific neurofilament and synaptic elements important in supporting and maintaining homeostasis in brain cells and neural signaling capabilities [ 51 , 52 , 57 , 58 , 59 , 60 , 71 ] ( Figure 2 ).…”

Section: Discussionmentioning

confidence: 99%

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

Zhao

Jaber

Pogue³

et al. 2022

IJMS

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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.

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“…5 Not only do the alterations of the microorganisms including Pg play a role in the development of periodontitis and Alzheimer's disease (AD) but also other microorganisms' disorders. [6][7][8] Patients with long-term periodontitis will further affect the ecological balance of the gut microbiota. 9 Some studies have shown that the gut microbiota communicates bidirectionally with the nervous system through regulating neurologic and immune-related signaling pathways, participating in the development and progression of various neurological diseases.…”

Section: Backg Rou N Dmentioning

confidence: 99%

“…The bacterium can also induce the production of pro‐inflammatory cytokines and chemokines 5 . Not only do the alterations of the microorganisms including Pg play a role in the development of periodontitis and Alzheimer's disease (AD) but also other microorganisms' disorders 6–8 . Patients with long‐term periodontitis will further affect the ecological balance of the gut microbiota 9 .…”

Section: Introductionmentioning

confidence: 99%

Potential diagnostic markers and therapeutic targets for periodontitis and Alzheimer's disease based on bioinformatics analysis

Yang,

Zhang,

Zhang

et al. 2024

J of Periodontal Research

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Background and ObjectiveAs a chronic inflammatory disease, periodontitis threatens oral health and is a risk factor for Alzheimer's disease (AD). There is growing evidence that these two diseases are closely related. However, current research is still incomplete in understanding the common genes and common mechanisms between periodontitis and AD. In this study, we aimed to identify common genes in periodontitis and AD and analyze the relationship between crucial genes and immune cells to provide new therapeutic targets for clinical treatment.Materials and MethodsWe evaluated differentially expressed genes (DEGs) specific to periodontitis and AD. Co‐expressed genes were identified by obtaining gene expression profile data from the Gene Expression Omnibus (GEO) database. Using the STRING database, protein–protein interaction (PPI) networks were constructed, and essential genes were identified. We also used four algorithms to identify critical genes and constructed regulatory networks. The association of crucial genes with immune cells and potential therapeutic effects was also assessed.ResultsPDGFRB, VCAN, TIMP1, CHL1, EFEMP2, and IGFBP5 were obtained as crucial common genes. Immune infiltration analysis showed that Natural killer cells and Myeloid‐derived suppressor cells were significantly differentially expressed in patients with PD and AD compared with the normal group. FOXC1 and GATA2 are important TFs for PD and AD. MiR‐23a, miR‐23b, miR‐23a, and miR‐23b were associated with AD and PD. Finally, the hub genes retrieved from the DSigDB database indicate multiple drug molecule and drug–target interactions.ConclusionThis study reveals commonalities in common hub genes and immune infiltration between periodontitis and AD, and the analysis of six hub genes and immune cells may provide new insights into potential therapeutic directions for the pathogenesis of periodontitis complicated by AD.

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The gut microbiome and Alzheimer’s disease: Complex and bidirectional interactions

Cited by 31 publications

References 349 publications

Why do anti-amyloid beta antibodies not work? Time to reconceptualize dementia pathophysiology by incorporating astrocyte melatonergic pathway desynchronization from amyloid-beta production

Why do anti-amyloid beta antibodies not work? Time to reconceptualize dementia pathophysiology by incorporating astrocyte melatonergic pathway desynchronization from amyloid-beta production

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

Potential diagnostic markers and therapeutic targets for periodontitis and Alzheimer's disease based on bioinformatics analysis

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