Dual-specificity phosphatase 26 (DUSP26) stimulates Aβ42 generation by promoting amyloid precursor protein axonal
Sunmin Jung1, Jihoon Nah1, Jonghee Han1
1Global Research Laboratory, School of Biological Science, Seoul National University, Gwanak-gu, Seoul, Korea.
Abstract:
Amyloid beta peptide (Aβ) is a pathological hallmark of Alzheimer's disease (AD) and is generated through the sequential cleavage of amyloid precursor protein (APP) by β- and γ-secretases. Hypoxia is a known risk factor for AD and stimulates Aβ generation by γ-secretase; however, the underlying mechanisms remain unclear. In this study, we showed that dual-specificity phosphatase 26 (DUSP26) regulates Aβ generation through changes in subcellular localization of the γ-secretase complex and its substrate C99 under hypoxic conditions. DUSP26 was identified as a novel γ-secretase regulator from a genome-wide functional screen using a cDNA expression library. The phosphatase activity of DUSP26 was required for the increase in Aβ42 generation through γ-secretase, but this regulation did not affect the amount of the γ-secretase complex. Interestingly, DUSP26 induced the accumulation of C99 in the axons by stimulating anterograde transport of C99-positive vesicles. Additionally, DUSP26 induced c-Jun N-terminal kinase (JNK) activation for APP processing and axonal transport of C99. Under hypoxic conditions, DUSP26 expression levels were elevated together with JNK activation, and treatment with JNK inhibitor SP600125, or the DUSP26 inhibitor NSC-87877, reduced hypoxia-induced Aβ generation by diminishing vesicle trafficking of C99 to the axons. Finally, we observed enhanced DUSP26 expression and JNK activation in the hippocampus of AD patients. Our results suggest that DUSP26 mediates hypoxia-induced Aβ generation through JNK activation, revealing a new regulator of γ-secretase-mediated APP processing under hypoxic conditions. We propose the role of phosphatase dual-specificity phosphatase 26 (DUSP26) in the selective regulation of Aβ42 production in neuronal cells under hypoxic stress. Induction of DUSP26 causes JNK-dependent shift in the subcellular localization of γ-secretase and C99 from the cell body to axons for Aβ42 generation. These findings provide a new strategy for developing new therapeutic targets to arrest AD progression.
Insights
Dual-specificity phosphatase 26 (DUSP26) regulates amyloid-beta (Aβ) generation under hypoxia by altering γ-secretase activity and C99 transport. This phosphatase, activated by hypoxia and c-Jun N-terminal kinase (JNK), offers a potential therapeutic target for Alzheimer's disease.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) peptide accumulation.
- Hypoxia is a risk factor for AD, increasing Aβ generation via γ-secretase, but mechanisms are unclear.
- Amyloid precursor protein (APP) is cleaved by β- and γ-secretases to produce Aβ.
Purpose of the Study:
- To investigate the role of dual-specificity phosphatase 26 (DUSP26) in regulating Aβ generation under hypoxic conditions.
- To elucidate the molecular mechanisms by which DUSP26 influences γ-secretase activity and APP processing.
Main Methods:
- Genome-wide functional screen to identify regulators of γ-secretase.
- Assessment of Aβ generation, C99 localization, and γ-secretase complex activity.
- Investigation of c-Jun N-terminal kinase (JNK) activation and its role in DUSP26-mediated effects.
- Analysis of DUSP26 and JNK expression in brain tissue from Alzheimer's disease patients.
Main Results:
- DUSP26 was identified as a novel regulator of Aβ generation, specifically increasing Aβ42 production.
- DUSP26 promotes the axonal accumulation of C99 by stimulating anterograde transport of C99-positive vesicles.
- DUSP26-induced Aβ generation is dependent on JNK activation and involves altered subcellular localization of γ-secretase components.
- Hypoxia elevates DUSP26 expression and JNK activation, leading to increased Aβ generation.
- Enhanced DUSP26 expression and JNK activation were observed in the hippocampus of AD patients.
Conclusions:
- DUSP26 mediates hypoxia-induced Aβ generation through JNK activation, revealing a new mechanism for γ-secretase regulation.
- DUSP26 influences the selective production of Aβ42 by altering the axonal transport of APP processing intermediates.
- Targeting DUSP26 or the JNK pathway presents a potential therapeutic strategy for Alzheimer's disease.
