Abstract
Axonal dystrophy is a swollen and tortuous neuronal process that contributes to synaptic alterations occurring in Alzheimer’s disease (AD). Previous study identified that brain-derived neurotrophic factor (BDNF) binds to tropomyosin-related kinase B (TrkB) at the axon terminal and then the signal is propagated along the axon to the cell body and affects neuronal function through retrograde transport. Therefore, this study was designed to identify a microRNA (miRNA) that alters related components of the transport machinery to affect BDNF retrograde signaling deficits in AD. Hippocampus tissues were isolated from APP/PS1 transgenic (AD-model) mice and C57BL/6J wild-type mice and subject to nicotinamide adenine dinucleotide phosphate and immunohistochemical staining. Autophagosome-lysosome fusion and nuclear translocation of BDNF was detected using immunofluorescence in HT22 cells. The interaction among miR-204, BIR repeat containing ubiquitin-conjugating enzyme (BRUCE) and Syntaxin 17 (STX17) was investigated using dual luciferase reporter gene assay and co-immunoprecipitation assay. The expression of relevant genes and proteins were determined by RT-qPCR and Western blot analysis. Knockdown of STX17 or BRUCE inhibited autophagosome–lysosome fusion and impacted axon growth in HT22 cells. STX17 immunoprecipitating with BRUCE and co-localization of them demonstrated BRUCE interacted with STX17. BRUCE was the target of miR-204, and partial loss of miR-204 by inhibitor promoted autophagosome–lysosome fusion to prevent axon dystrophy and accumulated BDNF nuclear translocation to rescue BDNF/TrkB signaling deficits in HT22 cells. The overall results demonstrated that inhibition of miR-204 prevents axonal dystrophy by blocking BRUCE interaction with STX17, which unraveled potential novel therapeutic targets for delaying AD.
Highlights
Dystrophic axons, known as dystrophic neuritis or neuroaxonal dystrophy, are considered one of the major neuropathological features of Alzheimer’s disease (AD)[1]
Previous researches have reported that retrograde transport of brain-derived neurotrophic factor (BDNF)-activated tropomyosin-related kinase B (TrkB) receptors was involved in the process of autophagosomes, which improves the neuronal complexity and preventing neurodegeneration in vivo, and the BDNF expression was modulated by sortilin-mediated trafficking and lysosomal degradation[8,9]
Axonal dystrophy, as one of the early pathological characteristics of neurodegenerative diseases including AD, is potentially causative in vesicular trafficking impairment, neuronal damage, and/or mortality[18]. It has been reported in a former study that the microtubule-stabilizing agent, Epothilone D could alleviate the disorders including axonal dysfunction and AD-like pathology in aged Tau transgenic mice[19]
Summary
Dystrophic axons (axonal dystrophy), known as dystrophic neuritis or neuroaxonal dystrophy, are considered one of the major neuropathological features of Alzheimer’s disease (AD)[1]. The two Interestingly, it has been revealed that the neurotrophins function as a crucial regulator of axon regeneration, especially brain-derived neurotrophic factor (BDNF)[6]. Previous researches have reported that retrograde transport of BDNF-activated tropomyosin-related kinase B (TrkB) receptors was involved in the process of autophagosomes, which improves the neuronal complexity and preventing neurodegeneration in vivo, and the BDNF expression was modulated by sortilin-mediated trafficking and lysosomal degradation[8,9]. The inhibitor of apoptosis family of proteins (IAP) BIR repeat-containing ubiquitin-conjugating enzyme (BRUCE) was reported to modulate the fusion of autophagosome and lysosome, and interacted with Syntaxin 17 (STX17), an important mediator in autophagosome–lysosome fusion[11]. From the findings above, it was hypothesized that the miR-204/BRUCE/STX17/BDNF axis may affect the development of dystrophic axons in AD by regulating the fusion of autophagosome and lysosome. The present study aimed to test this hypothesis and explore the underlying mechanism of axonal dystrophy in AD, which provides insight into the therapeutic targets for the treatment for AD
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