Rage-txnip Axis Drives Inflammation in Alzheimer`s by Targeting aβ to Mitochondria in Microglia

Abstract

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 demonstrated the role of RAGE-TXNIP axis in neuroinflammation in relation to amyloid-beta (Aβ) burden in both invivo and in-vitro models. In the hippocampus of 5xFAD mice, microglial activation correlates with increased TXNIP expression, and TXNIP silencing or its pharmacological inhibition prevented the neuroinflammation in those mice. TXNIP increased expression has been found also in human subjects affected by AD and other dementia when plasma samples were analyzed, suggesting TXNIP as a putative biomarker of neurodegeneration and cognitive decline. To better elucidate whether a mechanistic link between RAGE-TXNIP axis and AD exist, we investigated how TXNIP is involved in Aβ intracellular trafficking downstream RAGE. Indeed, TXNIP is an α-arrestin protein involved in endocytosis. We found TXNIP associated to RAGE and Aβ. RAGE-TXNIP axis was required for targeting Aβ into mitochondria, as shown in primed primary microglia exposed to Aβ dimers. Silencing of TXNIP or inhibition of RAGE activation reduced Aβ transport from the cellular surface to mitochondria. Detrimental effect of Aβ in mitochondria has been also confirmed by evaluating increased mitochondrial- and intracellular- oxidative stress. When RAGE-TXNIP axis is down-regulated, mitochondrial functionality was restored and Aβ toxicity was mitigated. Furthermore, Aβ transport into mitochondria and subsequent mitochondrial dysfunction drove inflammation in microglia cells via NLRP3 inflammasome activation, and down-regulation of RAGE-TXNIP axis was able to efficiently mitigate Aβ proinflammatory effect. Overall this data suggest RAGE-TXNIP axis is required for NLRP3 inflammasome activation induced by Aβ in microglia.Our work shed light on novel mechanism of action of RAGE-TXNIP axis in microglia, which is intertwined with Aβ and ultimately causes inflammation, suggesting TXNIP as a druggable target to be better deepened for AD.

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?

“…Our preliminary data show that silencing of TXNIP in an AD mice model prevents inflammation and altered microglia activation. In addition, our preliminary data suggest that TXNIP plasma levels correlates with cognitive decline [ 31 ].…”