TY - JOUR
T1 - Glial draper rescues Aβ toxicity in a Drosophila model of Alzheimer’s disease
AU - Ray, Arpita
AU - Speese, Sean D.
AU - Logan, Mary A.
N1 - Publisher Copyright:
© 2017 the authors.
PY - 2017/12/6
Y1 - 2017/12/6
N2 - 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 of Drosophila (both sexes). Neuronal expression of human Aβ42arc in adult flies results in robust Aβ 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 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 Aβ42arc exposure. Furthermore, Aβ42-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 Aβ 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.
AB - 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 of Drosophila (both sexes). Neuronal expression of human Aβ42arc in adult flies results in robust Aβ 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 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 Aβ42arc exposure. Furthermore, Aβ42-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 Aβ 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.
KW - Amyloid
KW - Autophagy
KW - Draper
KW - Drosophila
KW - Glia
UR - http://www.scopus.com/inward/record.url?scp=85037667754&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85037667754&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.0862-17.2017
DO - 10.1523/JNEUROSCI.0862-17.2017
M3 - Article
C2 - 29109235
AN - SCOPUS:85037667754
SN - 0270-6474
VL - 37
SP - 11881
EP - 11893
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 49
ER -