Glial Draper Rescues Aβ Toxicity in a Model of Alzheimer's Disease.
JOURNAL OF NEUROSCIENCE(2017)
摘要
Pathological hallmarks of Alzheimer's disease (AD) include amyloid-beta (A beta) plaques, neurofibrillary tangles, and reactive gliosis. Glial cells offer protection against AD by engulfing extracellular A beta peptides, but the repertoire of molecules required for glial recognition and destruction of A beta are still unclear. Here, we show that the highly conserved glial engulfment receptor Draper/MEGF10 provides neuro-protection in an AD model of Drosophila (both sexes). Neuronal expression of human A beta 42(arc) in adult flies results in robust A beta accumulation, neurodegeneration, locomotor dysfunction, and reduced lifespan. Notably, all of these phenotypes are more severe in draper mutant animals, whereas enhanced expression of glial Draper reverses A beta accumulation, as well as behavioral phenotypes. We also show that the signal transducer and activator of transcription (Stat92E), c-Jun N-terminal kinase (JNK)/AP-1 signaling, and expression of matrix metalloproteinase-1 (Mmp1) are activated downstream of Draper in glia in response to A beta 42(arc) exposure. Furthermore, A beta 42-induced upregulation of the phagolysosomal markers Atg8 and p62 was notably reduced in draper mutant flies. Based on our findings, we propose that glia clear neurotoxic A beta peptides in the AD model Drosophila brain through a Draper/STAT92E/JNK cascade that may be coupled to protein degradation pathways such as autophagy or more traditional phagolysosomal destruction methods.
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关键词
amyloid,autophagy,Draper,Drosophila,glia
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