Thioredoxin-Interacting Protein (TXNIP) Associated NLRP3 Inflammasome Activation in Human Alzheimer's Disease Brain

Lexiao Li, Saifudeen Ismael, Sanaz Nasoohi, Kazuko Sakata, Francesca-Fang Liao, Michael Mcdonald, Tauheed Ishrat

Research output: Contribution to journalArticle

Abstract

Alzheimer's disease (AD) is the most common form of age-associated dementia characterized by amyloid-β plaques and neurofibrillary tangles. Recent studies have demonstrated that thioredoxin-interacting protein (TXNIP), an endogenous regulator of redox/glucose induced stress and inflammation, is now known to be upregulated in stroke, traumatic brain injury, diabetes and AD. We hypothesized that TXNIP overexpression sustains neurodegeneration through activation of the nucleotide binding and oligomerization domain-like receptor protein 3 in human AD brains. We analyzed TXNIP and the components of the NLRP3 inflammasome in the cortex of postmortem human brain samples by western blotting, real-time PCR, and immunohistochemical techniques in comparison with age-matched non-demented controls. Our results demonstrate that TXNIP protein as well as its mRNA levels in the cortex was significantly upregulated in AD compared to control brains. Moreover, using double immunofluorescence staining, TXNIP and interlukin-1β (IL-1β) were co-localized near Aβ plaques and p-tau. These results suggest an association between TXNIP overexpression levels and AD pathogenesis. Further, a significant increased expression of cleaved caspase-1 and IL-1β, the products of inflammasome activation, was detected in the cortex of AD brains. Together, these findings suggest that TXNIP, an upstream promising new therapeutic target, is a molecular link between inflammation and AD. The significant contribution of TXNIP to AD pathology suggests that strategies focusing on specific targeting of the TXNIP-NLRP3 inflammasome may lead to novel therapies for the management of AD and other age-related dementias.

Original languageEnglish (US)
Pages (from-to)255-265
Number of pages11
JournalJournal of Alzheimer's Disease
Volume68
Issue number1
DOIs
StatePublished - Jan 1 2019

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Inflammasomes
Thioredoxins
Alzheimer Disease
Brain
Proteins
Dementia
Inflammation
Pyrin Domain-Containing 3 Protein NLR Family
Caspase 1
Neurofibrillary Tangles
Amyloid Plaques
Brain Diseases
Oxidation-Reduction
Fluorescent Antibody Technique
Real-Time Polymerase Chain Reaction
Nucleotides
Western Blotting
Stroke
Pathology
Staining and Labeling

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

Cite this

Thioredoxin-Interacting Protein (TXNIP) Associated NLRP3 Inflammasome Activation in Human Alzheimer's Disease Brain. / Li, Lexiao; Ismael, Saifudeen; Nasoohi, Sanaz; Sakata, Kazuko; Liao, Francesca-Fang; Mcdonald, Michael; Ishrat, Tauheed.

In: Journal of Alzheimer's Disease, Vol. 68, No. 1, 01.01.2019, p. 255-265.

Research output: Contribution to journalArticle

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