Unfolded protein response signaling by transcription factor XBP‐1 regulates ADAM10 and is affected in Alzheimer's disease

Abstract

In Alzheimer's disease (AD), disturbed homeostasis of the proteases competing for amyloid precursor protein processing has been reported: a disintegrin and metalloproteinase 10 (ADAM10), the physiological α-secretase, is decreased in favor of the amyloid-β-generating enzyme BACE-1. To identify transcription factors that modulate the expression of either protease, we performed a screening approach: 48 transcription factors significantly interfered with ADAM10/BACE-1-promoter activity. One selective inducer of ADAM10 gene expression is the X-box binding protein-1 (XBP-1). This protein regulates the unfolded protein-response pathway. We demonstrate that particularly the spliced XBP-1 variant dose dependently regulates ADAM10 expression, which can be synergistically enhanced by 100 nM insulin. Analysis of 2 different transgenic mouse models (APP/PS1 and 5xFAD) revealed that at early time points in pathology XBP-1 metabolism is induced. This is accompanied by a 2-fold augmented ADAM10 amount as compared with nontransgenic littermates (P=0.011). Along with aging of the mice, the system is counterregulated, and XBP-1 together with ADAM10 expression level decreased to ∼50% as compared with control animals. Analyses of expression levels in human AD brains showed that ADAM10 mRNA correlated with active XBP-1 (r=0.3120), but expression did not reach levels of healthy age-matched controls, suggesting deregulation of XBP-1 signaling. Our results demonstrate that XBP-1 is a driver of ADAM10 gene expression and that disturbance of this pathway might contribute to development or progression of AD.

APP mouse models for Alzheimer's disease preclinical studies

“…Non‐specific ER stress may arise in APP/PS‐overexpressing mice (Barbero‐Camps et al , 2014; Chaudhari et al , 2014; Reinhardt et al , 2014; Borkham‐Kamphorst et al , 2016; Saito et al , 2016). …”

Endoplasmic Reticulum Stress–Induced IRE1α Activation Mediates Cross-Talk of GSK-3β and XBP-1 To Regulate Inflammatory Cytokine Production

“…To further elucidate the potential signaling mechanisms involved in ER stress-induced TNF-a transcription in macrophages, we used STF-083010, a novel small-molecule inhibitor of IRE1a that inhibits IRE1a endonuclease activity (28,29). Treatment of RAW 264.7 macrophages with STF-083010 resulted in specific inhibition of TM-induced XBP-1 splicing (Fig.…”

The Transcription Factor XBP1 in Memory and Cognition: implications in Alzheimer’s Disease

“…In conclusion, this model implicates a dual mechanism wherein XBP1s synergistically promotes synaptic plasticity by fostering spine formation through Kalirin-7 signaling and lowers Aβ levels. Although the mechanisms underlying the XBP1s-dependent decrease of Aβ levels were not fully elucidated in that study, they may require recruitment and activation of enzymes that regulate Aβ levels (41,42,(76)(77)(78)(79) and/or APP metabolism/trafficking (40,(80)(81)(82).…”

“…These discrepancies likely reflect a compensatory mechanism triggered by acute exposure to Aβ oligomers, whereas chronic exposure to these neurotoxins, which is more reflective of the in vivo situation, causes an overdrive and collapse of the system. Direct evidence for such fluctuations comes from a recent study showing transient XBP1 activation at early time points in pathology followed by a decrease across different ages and AD models, as well as in humans (41). Notwithstanding the considerable knowledge of XBP1 biology, we do not yet know to what extent the various mediators of XBP1 signaling function through common, distinct or partly overlapping mechanisms.…”