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

Article type: Research Article

Authors: Li, Lexiao^{a; 1} | Ismael, Saifudeen^{a; 1} | Nasoohi, Sanaz^{a; d} | Sakata, Kazuko^{b; e} | Liao, Francesca-Fang^{b; e} | McDonald, Michael P.^{a; c; e} | Ishrat, Tauheed^{a; e; *}

Affiliations: [a] Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA | [b] Department of Pharmacology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA | [c] Department of Neurology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA | [d] Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran | [e] Neuroscience Institute, University of Tennessee Health Science Center, Memphis, TN, USA

Correspondence: [*] Correspondence to: Tauheed Ishrat, PhD, University of Tennessee Health Science Center, College of Medicine, Department of Anatomy and Neurobiology, 875 Monroe Avenue, Wittenborg Bldg, Room-231, Memphis, TN 38163, USA. Tel.: +1 901 448 2178; Fax: +1 901 448 7193; E-mail: tishrat@uthsc.edu.

Note: [1] These authors contributed equally to this work.

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.

Keywords: Alzheimer’s disease, amyloid plaques, hyperphosphorylated tau, NLRP3 inflammasome interlukin-1, thioredoxin-interacting protein

DOI: 10.3233/JAD-180814

Journal: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 255-265, 2019