| First Author | Sbai O | Year | 2022 |
| Journal | Cell Death Dis | Volume | 13 |
| Issue | 4 | Pages | 302 |
| PubMed ID | 35379773 | Mgi Jnum | J:386878 |
| Mgi Id | MGI:7265280 | Doi | 10.1038/s41419-022-04758-0 |
| Citation | Sbai O, et al. (2022) AGE-TXNIP axis drives inflammation in Alzheimer's by targeting Abeta to mitochondria in microglia. Cell Death Dis 13(4):302 |
| abstractText | 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 (Abeta) 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 Abeta. In particular, RAGE-TXNIP axis is required for targeting Abeta in mitochondria, leading to mitochondrial dysfunction and oxidative stress. Silencing of TXNIP or inhibition of RAGE activation reduces Abeta transport from the cellular surface to mitochondria, restores mitochondrial functionality, and mitigates Abeta toxicity. Furthermore, Abeta shuttling into mitochondria promotes Drp1 activation and exacerbates mitochondrial dysfunction, which induces NLRP3 inflammasome activation, leading to secretion of IL-1beta and activation of the pyroptosis-associated protein Gasdermin D (GSDMD). Downregulation of RAGE-TXNIP axis inhibits Abeta-induced mitochondria dysfunction, inflammation, and induction of GSDMD. Herein we unveil a new pathway driven by TXNIP that links the mitochondrial transport of Abeta to the activation of Drp1 and the NLRP3 inflammasome, promoting the secretion of IL-1beta 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 Abeta and ultimately causes mitochondria dysfunction and NLRP3 inflammasome cascade activation, suggesting TXNIP as a druggable target to be better deepened for AD. |
