The Emerging Role of Metabolism in Brain-Heart Axis: New Challenge for the Therapy and Prevention of Alzheimer Disease. May Thioredoxin Interacting Protein (TXNIP) Play a Role?

Perrone, Lorena; Valente, Mariarosaria

doi:10.3390/biom11111652

Cited by 8 publications

(6 citation statements)

References 129 publications

(169 reference statements)

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“…Oxidative stress activates the NLRP3 inflammasome through the Thioredoxin-Interacting Protein (TXNIP) [ 12 ], an inhibitor of the ROS scavenger Thioredoxin, and promotes oxidative stress [ 13 ]. TXNIP links oxidative stress to inflammation, leading to cellular dysfunction and it is implicated in several diseases that are at risk for AD [ 14 ]. Although recent studies are suggesting a possible role of TXNIP in AD [ 15 – 18 ] there is no study investigating the effect of TXNIP in activating the microglial NLRP3 inflammasome in an AD contest.…”

Section: Introductionmentioning

confidence: 99%

RAGE-TXNIP axis drives inflammation in Alzheimer’s by targeting Aβ to mitochondria in microglia

et al. 2022

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Alzheimer’s disease (AD) is the most common form of dementia characterized by progressive memory loss and cognitive decline. Although neuroinflammation and oxidative stress are well-recognized features of AD, their correlations with the early molecular events characterizing the pathology are not yet well clarified. Here, we characterize the role of RAGE–TXNIP axis in neuroinflammation in relation to amyloid-beta (Aβ) burden in both in vivo and in vitro models. In the hippocampus of 5xFAD mice microglial activation, cytokine secretion, and glial fibrillary acidic protein-enhanced expression are paralleled with increased TXNIP expression. TXNIP silencing or its pharmacological inhibition prevents neuroinflammation in those mice. TXNIP is also associated with RAGE and Aβ. In particular, RAGE–TXNIP axis is required for targeting Aβ in mitochondria, leading to mitochondrial dysfunction and oxidative stress. Silencing of TXNIP or inhibition of RAGE activation reduces Aβ transport from the cellular surface to mitochondria, restores mitochondrial functionality, and mitigates Aβ toxicity. Furthermore, Aβ shuttling into mitochondria promotes Drp1 activation and exacerbates mitochondrial dysfunction, which induces NLRP3 inflammasome activation, leading to secretion of IL-1β and activation of the pyroptosis-associated protein Gasdermin D (GSDMD). Downregulation of RAGE–TXNIP axis inhibits Aβ-induced mitochondria dysfunction, inflammation, and induction of GSDMD. Herein we unveil a new pathway driven by TXNIP that links the mitochondrial transport of Aβ to the activation of Drp1 and the NLRP3 inflammasome, promoting the secretion of IL-1β and the pyroptosis pathway associated with GSDMD cleavage. Altogether these data shed new light on a novel mechanism of action of RAGE–TXNIP axis in microglia, which is intertwined with Aβ and ultimately causes mitochondria dysfunction and NLRP3 inflammasome cascade activation, suggesting TXNIP as a druggable target to be better deepened for AD.

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Section: Introductionmentioning

confidence: 99%

RAGE-TXNIP axis drives inflammation in Alzheimer’s by targeting Aβ to mitochondria in microglia

et al. 2022

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“…RAGE promotes inflammation also by inducing the expression of Thioredoxin-Interacting Protein (TXNIP), which is an β-arrestincontaining protein that can bind to and inhibit the antioxidant protein thioredoxin (TXN), promoting oxidative stress (Perrone et al, 2009;Sbai et al, 2010). TXNIP is over expressed in the brain of AD patients and in several AD mice models and recent data suggest that it participates in AD pathophysiology (Melone et al, 2018;Nasoohi et al, 2018a,b;Wang et al, 2019;Tsubaki et al, 2020;Perrone and Valente, 2021;Zhang M. et al, 2021). TXNIP plays a key role in modulating the cell and body glucose homeostasis (Perrone and Valente, 2021).…”

Section: Role Of Drp1 In Admentioning

confidence: 99%

“…TXNIP is over expressed in the brain of AD patients and in several AD mice models and recent data suggest that it participates in AD pathophysiology (Melone et al, 2018;Nasoohi et al, 2018a,b;Wang et al, 2019;Tsubaki et al, 2020;Perrone and Valente, 2021;Zhang M. et al, 2021). TXNIP plays a key role in modulating the cell and body glucose homeostasis (Perrone and Valente, 2021). Notably, TXNIP plays a key role in activating the NLRP3 inflammasome (Schroder et al, 2010) and its association with NLRP3 has been shown also in AD (Li et al, 2019;Sbai et al, 2022).…”

Section: Role Of Drp1 In Admentioning

confidence: 99%

Is Drp1 a link between mitochondrial dysfunction and inflammation in Alzheimer’s disease?

Sbai,

Bazzani,

Tapaswi

et al. 2023

Front. Mol. Neurosci.

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Recent advances highlight that inflammation is critical to Alzheimer Disease (AD) pathogenesis. Indeed, several diseases characterized by inflammation are considered risk factors for AD, such as type 2 diabetes, obesity, hypertension, and traumatic brain injury. Moreover, allelic variations in genes involved in the inflammatory cascade are risk factors for AD. AD is also characterized by mitochondrial dysfunction, which affects the energy homeostasis of the brain. The role of mitochondrial dysfunction has been characterized mostly in neuronal cells. However, recent data are demonstrating that mitochondrial dysfunction occurs also in inflammatory cells, promoting inflammation and the secretion of pro-inflammatory cytokines, which in turn induce neurodegeneration. In this review, we summarize the recent finding supporting the hypothesis of the inflammatory-amyloid cascade in AD. Moreover, we describe the recent data that demonstrate the link between altered mitochondrial dysfunction and the inflammatory cascade. We focus in summarizing the role of Drp1, which is involved in mitochondrial fission, showing that altered Drp1 activation affects the mitochondrial homeostasis and leads to the activation of the NLRP3 inflammasome, promoting the inflammatory cascade, which in turn aggravates Amyloid beta (Ab) deposition and tau-induced neurodegeneration, showing the relevance of this pro-inflammatory pathway as an early event in AD.

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“…Neurodegenerative diseases are characterised by progressive atrophy and loss of neuronal function. Although several familiar forms of neurodegenerative diseases have been characterised by analysing the function of mutant genes, the relevance of altered metabolic function as a key factor promoting the onset and progression of sporadic neurodegenerative diseases is emerging [ 10 ]. In this context, mitochondrial alterations promote key events occurring during ageing and in neurodegeneration.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial DNA Repair in Neurodegenerative Diseases and Ageing

Bazzani

Redin

McHale

et al. 2022

IJMS

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Mitochondria are the only organelles, along with the nucleus, that have their own DNA. Mitochondrial DNA (mtDNA) is a double-stranded circular molecule of ~16.5 kbp that can exist in multiple copies within the organelle. Both strands are translated and encode for 22 tRNAs, 2 rRNAs, and 13 proteins. mtDNA molecules are anchored to the inner mitochondrial membrane and, in association with proteins, form a structure called nucleoid, which exerts a structural and protective function. Indeed, mitochondria have evolved mechanisms necessary to protect their DNA from chemical and physical lesions such as DNA repair pathways similar to those present in the nucleus. However, there are mitochondria-specific mechanisms such as rapid mtDNA turnover, fission, fusion, and mitophagy. Nevertheless, mtDNA mutations may be abundant in somatic tissue due mainly to the proximity of the mtDNA to the oxidative phosphorylation (OXPHOS) system and, consequently, to the reactive oxygen species (ROS) formed during ATP production. In this review, we summarise the most common types of mtDNA lesions and mitochondria repair mechanisms. The second part of the review focuses on the physiological role of mtDNA damage in ageing and the effect of mtDNA mutations in neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. Considering the central role of mitochondria in maintaining cellular homeostasis, the analysis of mitochondrial function is a central point for developing personalised medicine.

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The Emerging Role of Metabolism in Brain-Heart Axis: New Challenge for the Therapy and Prevention of Alzheimer Disease. May Thioredoxin Interacting Protein (TXNIP) Play a Role?

Cited by 8 publications

References 129 publications

RAGE-TXNIP axis drives inflammation in Alzheimer’s by targeting Aβ to mitochondria in microglia

RAGE-TXNIP axis drives inflammation in Alzheimer’s by targeting Aβ to mitochondria in microglia

Is Drp1 a link between mitochondrial dysfunction and inflammation in Alzheimer’s disease?

Mitochondrial DNA Repair in Neurodegenerative Diseases and Ageing

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