Glial Draper Rescues Aβ Toxicity in aDrosophilaModel of Alzheimer's Disease
| Autor: | Sean D. Speese, Mary A. Logan, Arpita Ray |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Arc (protein) biology Amyloid Amyloid beta General Neuroscience fungi Neurodegeneration Autophagy Protein degradation medicine.disease Neuroprotection 03 medical and health sciences 030104 developmental biology Downregulation and upregulation medicine biology.protein Neuroscience |
| Zdroj: | The Journal of Neuroscience. 37:11881-11893 |
| ISSN: | 1529-2401 0270-6474 |
| Popis: | Pathological hallmarks of Alzheimer's disease (AD) include amyloid-β (Aβ) plaques, neurofibrillary tangles, and reactive gliosis. Glial cells offer protection against AD by engulfing extracellular Aβ peptides, but the repertoire of molecules required for glial recognition and destruction of Aβ are still unclear. Here, we show that the highly conserved glial engulfment receptor Draper/MEGF10 provides neuroprotection in an AD model ofDrosophila(both sexes). Neuronal expression of human Aβ42arcin adult flies results in robust Aβ accumulation, neurodegeneration, locomotor dysfunction, and reduced lifespan. Notably, all of these phenotypes are more severe indrapermutant animals, whereas enhanced expression of glial Draper reverses Aβ 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 Aβ42arcexposure. Furthermore, Aβ42-induced upregulation of the phagolysosomal markers Atg8 and p62 was notably reduced indrapermutant flies. Based on our findings, we propose that glia clear neurotoxic Aβ peptides in the AD modelDrosophilabrain through a Draper/STAT92E/JNK cascade that may be coupled to protein degradation pathways such as autophagy or more traditional phagolysosomal destruction methods.SIGNIFICANCE STATEMENTAlzheimer's disease (AD) and similar dementias are common incurable neurodegenerative disorders in the aging population. As the primary immune responders in the brain, glial cells are implicated as key players in the onset and progression of AD and related disorders. Here we show that the glial engulfment receptor Draper is protective in aDrosophilamodel of AD, reducing levels of amyloid β (Aβ) peptides, reversing locomotor defects, and extending lifespan. We further show that protein degradation pathways are induced downstream of Draper in AD model flies, supporting a model in which glia engulf and destroy Aβ peptides to reduce amyloid-associated toxicity. |
| Databáze: | OpenAIRE |
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