Insulin Resistance at the Crossroad of Alzheimer Disease Pathology: A Review

Berlanga‐Acosta, Jorge; Guillén-Nieto, Gerardo; Rodríguez-Rodríguez, Nadia; Bringas‐Vega, Maria L.; García-del-Barco-Herrera, Diana; Berlanga-Saez, Jorge O.; García‐Ojalvo, Ariana; Valdés-Sosa, Mitchell; Valdés‐Sosa, Pedro A.

doi:10.3389/fendo.2020.560375

Cited by 59 publications

(46 citation statements)

References 283 publications

(329 reference statements)

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“…However, in the course of metabolic diseases related to obesity, both elevated cytokines (e.g., TNFα) and free fatty acid (FFA) trigger serine phosphorylation of IRS-1 by stress kinases, resulting in the development of insulin resistance [60] (Figure 2). The major intracellular stress kinase that links TNFα to inhibitory serine phosphorylation of IRS-1 in T2DM and obesity is the c-Jun N-terminal kinase (JNK) family of MAPK [49,61]. Moreover, the activation of the JNK may serve as a bridge between peripheral and central insulin resistance.…”

Section: Malfunction Of Insulin Signalingmentioning

confidence: 99%

“…Of note, studies revealed that both oligomers of Aβ and a high-fat diet stimulated the JNK phosphorylation in the hippocampal neurons, leading to the downregulation of insulin signaling [63,64]. Deficiency in the insulin-IRS-PI3K-Akt signaling pathway could result in the activation of GSK3β, promotion of hyperphosphorylation of tau protein, and the occurrence The major intracellular stress kinase that links TNFα to inhibitory serine phosphorylation of IRS-1 in T2DM and obesity is the c-Jun N-terminal kinase (JNK) family of MAPK [49,61]. Moreover, the activation of the JNK may serve as a bridge between peripheral and central insulin resistance.…”

Section: Malfunction Of Insulin Signalingmentioning

confidence: 99%

“…An increasing number of studies indicate that sporadic AD etiopathogenesis may also be associated with dysfunctional brain insulin signaling and the subsequent disruption of glucose metabolism [ 49 ]. Interestingly, the positron emission tomography studies ( 18 F deoxyglucose positron emission tomography; 18FDG-PET) showed a reduced brain glucose uptake in the hippocampus and brain cortex of familial and sporadic AD subjects [ 50 , 51 ].…”

Section: Glucose Metabolism In the Brainmentioning

confidence: 99%

“…The major intracellular stress kinase that links TNFα to inhibitory serine phosphorylation of IRS-1 in T2DM and obesity is the c-Jun N-terminal kinase (JNK) family of MAPK [ 49 , 61 ]. Moreover, the activation of the JNK may serve as a bridge between peripheral and central insulin resistance.…”

Section: Insulin Resistance As a Common Factor Linking Obesity T2dm And Admentioning

confidence: 99%

“…Deficiency in the insulin-IRS-PI3K-Akt signaling pathway could result in the activation of GSK3β, promotion of hyperphosphorylation of tau protein, and the occurrence of neuronal dysfunction [ 38 ]. Additionally, JNK plays a role in mediating degeneration and apoptosis in the brain as well as in impairing neuronal insulin axis physiology [ 49 ]. Further, postmortem brains in the AD model showed increased serine phosphorylation of IRS-1 as well as JNK expression [ 64 ].…”

Section: Insulin Resistance As a Common Factor Linking Obesity T2dm And Admentioning

confidence: 99%

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Inflammasome NLRP3 Potentially Links Obesity-Associated Low-Grade Systemic Inflammation and Insulin Resistance with Alzheimer’s Disease

Litwiniuk

Bik

Kalisz

et al. 2021

IJMS

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Alzheimer’s disease (AD) is the most common form of neurodegenerative dementia. Metabolic disorders including obesity and type 2 diabetes mellitus (T2DM) may stimulate amyloid β (Aβ) aggregate formation. AD, obesity, and T2DM share similar features such as chronic inflammation, increased oxidative stress, insulin resistance, and impaired energy metabolism. Adiposity is associated with the pro-inflammatory phenotype. Adiposity-related inflammatory factors lead to the formation of inflammasome complexes, which are responsible for the activation, maturation, and release of the pro-inflammatory cytokines including interleukin-1β (IL-1β) and interleukin-18 (IL-18). Activation of the inflammasome complex, particularly NLRP3, has a crucial role in obesity-induced inflammation, insulin resistance, and T2DM. The abnormal activation of the NLRP3 signaling pathway influences neuroinflammatory processes. NLRP3/IL-1β signaling could underlie the association between adiposity and cognitive impairment in humans. The review includes a broadened approach to the role of obesity-related diseases (obesity, low-grade chronic inflammation, type 2 diabetes, insulin resistance, and enhanced NLRP3 activity) in AD. Moreover, we also discuss the mechanisms by which the NLRP3 activation potentially links inflammation, peripheral and central insulin resistance, and metabolic changes with AD.

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Section: Malfunction Of Insulin Signalingmentioning

confidence: 99%

Section: Malfunction Of Insulin Signalingmentioning

confidence: 99%

Section: Glucose Metabolism In the Brainmentioning

confidence: 99%

Section: Insulin Resistance As a Common Factor Linking Obesity T2dm And Admentioning

confidence: 99%

Section: Insulin Resistance As a Common Factor Linking Obesity T2dm And Admentioning

confidence: 99%

See 3 more Smart Citations

Inflammasome NLRP3 Potentially Links Obesity-Associated Low-Grade Systemic Inflammation and Insulin Resistance with Alzheimer’s Disease

Litwiniuk

Bik

Kalisz

et al. 2021

IJMS

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The imbalance of Th17/Treg via STAT3 activation modulates cognitive impairment inP. gingivalis LPS-induced periodontitis mice

Zhang

Qiu

et al. 2021

Journal of Leukocyte Biology

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Periodontitis is one of the most common oral diseases worldwide, and it is associated with various systemic diseases, including cognitive diseases. STAT3 regulates the inflammatory cascade and influences adaptive immunity by modulating Th17/Treg cell differentiation. In this study, we aimed to explore the effect of adaptive immunity inside and outside the brain on the association between periodontitis and cognitive impairment and understand the role of the STAT3 signaling pathway. We established Porphyromonas gingivalis LPS‐induced periodontitis mice models by injecting P. gingivalis LPS into the gingival sulcus of mice. Behavioral tests showed that learning and memory abilities were impaired. The flow cytometry data showed an imbalance in the Th17/Treg ratio in the blood and brain samples of the mice. The expression of Th17‐related cytokines (IL‐1β, IL‐17A, IL‐21, and IL‐22) increased, whereas that of Treg‐related cytokines (IL‐2 and IL‐10) decreased in both the blood and the brain. The level of LPS increased and the STAT3 signaling pathway was activated during this process. These effects were reversed by C188‐9, a STAT3 inhibitor. In conclusion, P. gingivalis LPS‐induced periodontitis may promote the occurrence and progression of cognitive impairment by modulating the Th17/Treg balance inside and outside the brain. The STAT3 signaling pathway may have immunoregulatory effects on the mouth‐to‐brain axis.

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Structural models of viral insulin‐like peptides and their analogs

Gorai

Vashisth

2022

Proteins

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The insulin receptor (IR), the insulin-like growth factor-1 receptor (IGF1R), and the insulin/IGF1 hybrid receptors (hybR) are homologous transmembrane receptors. The peptide ligands, insulin and IGF1, exhibit significant structural homology and can bind to each receptor via site-1 and site-2 residues with distinct affinities. The variants of the Iridoviridae virus family show capability in expressing single-chain insulin/IGF1 like proteins, termed viral insulin-like peptides (VILPs), which can stimulate receptors from the insulin family. The sequences of VILPs lacking the central C-domain (dcVILPs) are known, but their structures in unbound and receptor-bound states have not been resolved to date. We report all-atom structural models of three dcVILPs (dcGIV, dcSGIV, and dcLCDV1) and their complexes with the receptors (μIR, μIGF1R, and μhybR), and probed the peptide/receptor interactions in each system using allatom molecular dynamics (MD) simulations. Based on the nonbonded interaction energies computed between each residue of peptides (insulin and dcVILPs) and the receptors, we provide details on residues establishing significant interactions. The observed site-1 insulin/μIR interactions are consistent with previous experimental studies, and a residue-level comparison of interactions of peptides (insulin and dcVILPs) with the receptors revealed that, due to sequence differences, dcVILPs also establish some interactions distinct from those between insulin and IR. We also designed insulin analogs and report enhanced interactions between some analogs and the receptors.

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Insulin Resistance at the Crossroad of Alzheimer Disease Pathology: A Review

Cited by 59 publications

References 283 publications

Inflammasome NLRP3 Potentially Links Obesity-Associated Low-Grade Systemic Inflammation and Insulin Resistance with Alzheimer’s Disease

Inflammasome NLRP3 Potentially Links Obesity-Associated Low-Grade Systemic Inflammation and Insulin Resistance with Alzheimer’s Disease

The imbalance of Th17/Treg via STAT3 activation modulates cognitive impairment inP. gingivalis LPS-induced periodontitis mice

Structural models of viral insulin‐like peptides and their analogs

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