DEAD-Box Helicase 17 Promotes Amyloidogenesis by Regulating BACE1 Translation

Abstract

Amyloidogenesis is one of the key pathophysiological changes in Alzheimer’s disease (AD). Accumulation of the toxic Aβ results from the catalytic processing of β-amyloid precursor protein (APP) associated β-amyloid converting enzyme 1 (BACE1) activity. It is reported that dead-box helicase 17 (DDX17) controls RNA metabolism and is involved in the development of multiple diseases. However, whether DDX17 might play a role in amyloidogenesis has not been documented. In the present study, we found that DDX17 protein level was significantly increased in HEK and SH-SY5Y cells that stably express full-length APP (HEK-APP and Y5Y-APP) and in the brain of APP/PS1 mice, an animal model of AD. DDX17 knockdown, as opposed to DDX17 overexpression, markedly reduced the protein levels of BACE1 and the β-amyloid peptide (Aβ) in Y5Y-APP cells. We further found that DDX17-mediated enhancement of BACE1 was selectively attenuated by translation inhibitors. Specifically, DDX17 selectively interacted with the 5′ untranslated region (5′UTR) of BACE1 mRNA, and deletion of the 5′UTR abolished the effect of DDX17 on luciferase activity or protein level of BACE1. Here, we show that the enhanced expression of DDX17 in AD was associated with amyloidogenesis; through the 5′UTR-dependent BACE1 translation, DDX17 might serve as an important mediator contributing to the progression of AD.

DEAD Box Helicase 24 Is Increased in the Brain in Alzheimer’s Disease and AppN-LF Mice and Influences Presymptomatic Pathology

“…These data indicate that the increased levels of DDX24 occur early during the culturing of hippocampal neurons but disappear when the neuron is mature, which reflects the change of DDX24 in the brains of App NL-F mice. Furthermore, DEAD Box Helicase 17, a similar protein to DDX24, has been implicated in amyloidosis, suggesting that the DEAD box helicase family might influence AD pathology [25].…”

Unraveling the therapeutic potential of ginsenoside compound Mc1 in Alzheimer’s disease: Exploring the role of AMPK/SIRT1/NF-κB signaling pathway and mitochondrial function

“…Neuroplasticity deficits, characterized by synaptic loss and neuronal shrinkage in the prefrontal cortex and hippocampus, significantly contribute to the impairment of learning and memory. 38,39 The accumulation of Aβ within hippocampal neurons has detrimental effects on synaptic plasticity. 40 However, there is currently no available information on the potential impact of GCMc1 in this context.…”