Dual-specificity phosphatase 26 (DUSP26) stimulates A beta 42 generation by promoting amyloid precursor protein axonal transport during hypoxia

摘要

Amyloid beta peptide (A beta) is a pathological hallmark of Alzheimer's disease (AD) and is generated through the sequential cleavage of amyloid precursor protein (APP) by beta- and y-secretases. Hypoxia is a known risk factor for AD and stimulates A beta generation by gamma-secretase; however, the underlying mechanisms remain unclear. In this study, we showed that dual-specificity phosphatase 26 (DUSP26) regulates A beta generation through changes in subcellular localization of the gamma-secretase complex and its substrate C99 under hypoxic conditions. DUSP26 was identified as a novel gamma-secretase regulator from a genome-wide functional screen using a cDNA expression library. The phosphatase activity of DUSP26 was required for the increase in A1342 generation through y-secretase, but this regulation did not affect the amount of the y-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 Ali 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 Alt generation through JNK activation, revealing a new regulator of 7secretase-mediated APP processing under hypoxic conditions.