Role of Toll Like Receptor 4 in Alzheimer’s Disease

Calvo-Rodríguez, María; García-Rodríguez, Carmen; Villalobos, Carlos; Núñez, Lucı́a

doi:10.3389/fimmu.2020.01588

Cited by 82 publications

(77 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, TLR4-mediated induction of apoptosis is observed mostly in aging and not young neurons 36 . TLR4 mediated signaling, via still unclear mechanisms, seems to contribute to the pathology of age-related neurodegenerative diseases, including AD 36 . Using TLR4 antagonists, such as IBU, could offer an efficient means to prevent the damaging events associated with neuroinflammation in AD.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Multi-scale predictive modeling discovers Ibudilast as a polypharmacological agent to improve hippocampal-dependent spatial learning and memory and mitigate plaque and tangle pathology in a transgenic rat model of Alzheimer’s disease

Oliveros

Chaudry

et al. 2021

Preprint

View full text Add to dashboard Cite

Alzheimer's disease (AD) is a multifactorial disease that exhibits cognitive deficits, neuronal loss, amyloid plaques, neurofibrillary tangles and neuroinflammation in the brain. We developed a multi-scale predictive modeling strategy that integrates machine learning with biophysics and systems pharmacology to model drug actions from molecular interactions to phenotypic responses. We predicted that ibudilast (IBU), a phosphodiesterase inhibitor and toll-like receptor 4 (TLR4) antagonist, inhibited multiple kinases (e.g., IRAK1 and GSG2) as off-targets, modulated multiple AD-associated pathways, and reversed AD molecular phenotypes. We address for the first time the efficacy of ibudilast (IBU) in a transgenic rat model of AD. IBU-treated transgenic rats showed improved cognition and reduced hallmarks of AD pathology. RNA sequencing analyses in the hippocampus showed that IBU affected the expression of pro-inflammatory genes in the TLR signaling pathway. Our results identify IBU as a potential therapeutic to be repurposed for reducing neuroinflammation in AD by targeting TLR signaling.

show abstract

Section: Discussionmentioning

confidence: 99%

“…However, their significance is crucial as IBU is a TLR4 antagonist. Interestingly, TLR4-mediated induction of apoptosis is observed mostly in aging and not young neurons 36 . TLR4 mediated signaling, via still unclear mechanisms, seems to contribute to the pathology of age-related neurodegenerative diseases, including AD 36 .…”

Section: Discussionmentioning

confidence: 99%

Multi-scale predictive modeling discovers Ibudilast as a polypharmacological agent to improve hippocampal-dependent spatial learning and memory and mitigate plaque and tangle pathology in a transgenic rat model of Alzheimer’s disease

Oliveros

Chaudry

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Thus far, several studies have been conducted trying to find how autophagy is regulated in AD. TLR4 is suggested as one of the main mediators of neuronal damage in AD [ 348 ]. Qin et al reported that stimulation of TLR4 by LPS in tau-transgenic mice resulted in enhancement of neuronal autophagy, which was associated with a reduction of cerebral p-Tau proteins and improved cognitive function [ 349 ].…”

Section: Autophagy and Neuroinflammation In Admentioning

confidence: 99%

Alzheimer’s Disease Pathogenesis: Role of Autophagy and Mitophagy Focusing in Microglia

Eshraghi

Adlimoghaddam

Mahmoodzadeh

et al. 2021

IJMS

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is a debilitating neurological disorder, and currently, there is no cure for it. Several pathologic alterations have been described in the brain of AD patients, but the ultimate causative mechanisms of AD are still elusive. The classic hallmarks of AD, including am-yloid plaques (Aβ) and tau tangles (tau), are the most studied features of AD. Unfortunately, all the efforts targeting these pathologies have failed to show the desired efficacy in AD patients so far. Neuroinflammation and impaired autophagy are two other main known pathologies in AD. It has been reported that these pathologies exist in AD brain long before the emergence of any clinical manifestation of AD. Microglia are the main inflammatory cells in the brain and are considered by many researchers as the next hope for finding a viable therapeutic target in AD. Interestingly, it appears that the autophagy and mitophagy are also changed in these cells in AD. Inside the cells, autophagy and inflammation interact in a bidirectional manner. In the current review, we briefly discussed an overview on autophagy and mitophagy in AD and then provided a comprehensive discussion on the role of these pathways in microglia and their involvement in AD pathogenesis.

show abstract

“…The involvement of TLR4/MD-2 complex in neuroinflammation has been reported in recent years [ 20 – 22 ]. TLR4/MD-2 complex is linked with memory deficit in the presence of Aβ oligomers (Aβo) [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

Insights from molecular docking and molecular dynamics on the potential of vitexin as an antagonist candidate against lipopolysaccharide (LPS) for microglial activation in neuroinflammation

et al. 2021

View full text Add to dashboard Cite

Background Neuroinflammation has been identified to be the key player in most neurodegenerative diseases. If neuroinflammation is left to be unresolved, chronic neuroinflammation will be establish. Such situation is due to the overly-activated microglia which have the tendency to secrete an abundance amount of pro-inflammatory cytokines into the neuron microenvironment. The abundance of pro-inflammatory cytokines will later cause toxic and death to neurons. Toll-like receptor 4 (TLR4)/MD-2 complex found on the cell surface of microglia is responsible for the attachment of LPS and activation of nuclear factor-κB (NF-κB) downstream signalling pathway. Albeit vitexin has been shown to possess anti-inflammatory property, however, little is known on its ability to bind at the binding site of TLR4/MD-2 complex of microglia as well as to be an antagonist for LPS. Results The present study reveals that both vitexin and donepezil are able to bind at the close proximity of LPS binding site located at the TLR4/MD-2 complex with the binding energy of − 4.35 and − 9.14 kcal/mol, respectively. During molecular dynamic simulations, both vitexin and donepezil formed stable complex with TLR4/MD-2 throughout the 100 ns time length with the root mean square deviation (RMSD) values of 2.5 Å and 4.0 Å, respectively. The root mean square fluctuation (RMSF) reveals that both compounds are stable. Interestingly, the radius of gyration (rGyr) for donepezil shows notable fluctuations when compare with vitexin. The MM-GBSA results showed that vitexin has higher binding energy in comparison with donepezil. Conclusions Taken together, the findings suggest that vitexin is able to bind at the binding site of TLR4/MD-2 complex with more stability than donepezil throughout the course of 100 ns simulation. Hence, vitexin has the potential to be an antagonist candidate for LPS.

show abstract

Role of Toll Like Receptor 4 in Alzheimer’s Disease

Cited by 82 publications

References 33 publications

Multi-scale predictive modeling discovers Ibudilast as a polypharmacological agent to improve hippocampal-dependent spatial learning and memory and mitigate plaque and tangle pathology in a transgenic rat model of Alzheimer’s disease

Multi-scale predictive modeling discovers Ibudilast as a polypharmacological agent to improve hippocampal-dependent spatial learning and memory and mitigate plaque and tangle pathology in a transgenic rat model of Alzheimer’s disease

Alzheimer’s Disease Pathogenesis: Role of Autophagy and Mitophagy Focusing in Microglia

Insights from molecular docking and molecular dynamics on the potential of vitexin as an antagonist candidate against lipopolysaccharide (LPS) for microglial activation in neuroinflammation

Contact Info

Product

Resources

About