Thioredoxin-Interacting Protein (TXNIP) with Focus on Brain and Neurodegenerative Diseases

Abstract

The development of new therapeutic approaches to diseases relies on the identification of key molecular targets involved in amplifying disease processes. One such molecule is thioredoxin-interacting protein (TXNIP), also designated thioredoxin-binding protein-2 (TBP-2), a member of the α-arrestin family of proteins and a central regulator of glucose and lipid metabolism, involved in diabetes-associated vascular endothelial dysfunction and inflammation. TXNIP sequesters reduced thioredoxin (TRX), inhibiting its function, resulting in increased oxidative stress. Many different cellular stress factors regulate TXNIP expression, including high glucose, endoplasmic reticulum stress, free radicals, hypoxia, nitric oxide, insulin, and adenosine-containing molecules. TXNIP is also directly involved in inflammatory activation through its interaction with the nucleotide-binding domain, leucine-rich-containing family, and pyrin domain-containing-3 (NLRP3) inflammasome complex. Neurodegenerative diseases such as Alzheimer’s disease have significant pathologies associated with increased oxidative stress, inflammation, and vascular dysfunctions. In addition, as dysfunctions in glucose and cellular metabolism have been associated with such brain diseases, a role for TXNIP in neurodegeneration has actively been investigated. In this review, we will focus on the current state of the understanding of possible normal and pathological functions of TXNIP in the central nervous system from studies of in vitro neural cells and the brains of humans and experimental animals with reference to other studies. As TXNIP can be expressed by neurons, microglia, astrocytes, and endothelial cells, a complex pattern of regulation and function in the brain is suggested. We will examine data suggesting TXNIP as a therapeutic target for neurodegenerative diseases where further research is needed.

Role of Thioredoxin-Interacting Protein in Diseases and Its Therapeutic Outlook

“…The involvement of TXNIP in AD is mostly associated with inflammation; accumulated data indicate overexpression of TXNIP in the brain via amyloid-β (Aβ) exposure [108,109], and also TXNIP remained an exclusive marker in microglia, neurons, astrocytes, and endothelial cells [110]. The prevalent idea proposes that TXNIP is an essential mediator of NLRP3 inflammasome activation and the eventual formation of activated caspase 1 [93].…”

Endothelial Thioredoxin-Interacting Protein Depletion Reduces Hemorrhagic Transformation in Hyperglycemic Mice after Embolic Stroke and Thrombolytic Therapy

“…Chronic hyperglycemia has long been associated with brain endothelial complications in diabetes and metabolic disorders through different signaling cascades, including the TXNIP/NLRP-3 pathway [5,18]. Several studies have implicated the involvement of HG in neurovascular damage following ischemic stroke, HG further increased the oxidative stress, inflammatory responses as well as increased the BBB permeability [33].…”

“…However, there is still a gap in our understanding of how inflammation and redox signaling contributes to neurovascular damage, particularly in HG conditions, to sustain neuronal injury and worsen stroke outcome. Thioredoxin-interacting protein (TXNIP) has emerged as a key pathological regulator of various diseases, associated with glucose and lipid abnormalities and inflammation, including diabetes mellitus and cerebrovascular diseases [17,18]. TXNIP is an endogenous inhibitor of the thioredoxin (TRX), that modulates the cellular redox signaling state and induces oxidative damage [19].…”

Activation of NLRP3 Inflammasome and Onset of Alzheimer’s Disease

“…It is speculated that the activation of NLRP3 inflammasome in human AD brain may promote the occurrence of neurodegeneration. TXNIP has potential as a molecular link between chronic immune inflammation and AD, and is expected to be a new therapeutic target in the future ( 52 , 53 ).…”