Investigating the Role of Draper/MEGF10 in Alzheimer's Disease

Oregon Health & Science University, Portland OR

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Abstract

Alzheimer's disease (AD) and similar dementias present substantive challenges to patients and families, including medical, emotional, and fiscal hardships. Understanding the basic molecular underpinnings associated with AD progression is imperative to develop targeted strategies to intervene before notable cognitive decline occurs in patients. Glial cells, the first immune responders in the brain, are believed to influence AD pathology, although the molecular and cellular details are still unclear. Healthy glial cells can efficiently engulf amyloid-beta (A?), one of the major neurotoxic proteins that forms aggregates in the AD brain, and it has been proposed that defects in glial clearance of A? may contribute to the onset or advancement of AD. How do glia clear A? in the brain? What are the molecules and signaling pathways that govern glial recognition and engulfment of A?? Finally, what is the fate of A? once it has been internalized by glial cells? Using a well-established AD model in Drosophila melanogaster, we have identified the Draper receptor as a novel neuroprotective molecule against A?-induced toxicity. Draper is a highly conserved glial engulfment receptor required for glial phagocytic clearance of apoptotic neurons and degenerating axons. Notably, the role of Draper or the mammalian orthologs (MEGF10/Jedi) in glial clearance of A? function have never been explored in vivo. Here, we show that loss of glial Draper results in greater A? accumulation, exacerbates locomotor defects, and further reduces lifespan, while activation of glial Draper reverses these molecular and behavioral phenotypes. Our preliminary work also suggests that Draper-dependent activation of autophagy pathways may influence the progression of A?-induced CNS dysfunction. Thus, we hypothesize that glial cells utilize the Draper receptor to internalize and/or degrade neurotoxic A? peptides in the adult brain and that Draper activity attenuates A?-induced phenotypes. Draper activates several downstream signaling pathways, including altered cytoskeletal remodeling, autophagy, and transcription (specifically, STAT92E and AP-1). In Aim 1, we will use genetic and microscopy methods, as well as behavioral assays, to interrogate known downstream signaling effectors of Draper to determine which pathways protect against A? accumulation, motor defects, and reduced longevity. In Aim 2, we will investigate the possibility that Draper influences A? propagation throughout the CNS. More specifically, we propose that glial Draper/autophagy promotes A? destruction, thereby inhibiting A? peptide spreading. Using in vivo genetic manipulations and super resolution microscopy, we will inhibit glial Draper and autophagy pathways to determine if A? propagates more readily in the adult brain. This work will rapidly offer new molecular insight into how Draper/MEGF10 is coupled to AD progression and, more broadly, will provide a significant advancement in our understanding of how glial immunity is linked AD, as well as other proteinopathies.