Netrin-1 receptor UNC5C cleavage by active-secretase enhances neurodegeneration, promoting Alzheimer's disease pathologies

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Abstract

Netrin-1, a family member of laminin-related secreted proteins, mediates axon guidance and cell migration during neural development. T835M mutation in netrin receptor UNC5C predisposes to the late-onset Alzheimer's disease (AD) and increases neuronal cell death. However, it remains unclear how this receptor is molecularly regulated in AD. Here, we show that-secretase selectively cleaves UNC5C and escalates its proapoptotic activity, facilitating neurodegeneration in AD. Netrin deficiency activates-secretase that specifically cuts UNC5C at N467 and N547 residues and enhances subsequent caspase-3 activation, additively augmenting neuronal cell death. Blockade of-secretase cleavage of UNC5C diminishes T835M mutant's proapoptotic activity. Viral expression of-secretase-Truncated UNC5C fragments into APP/PS1 mice strongly accelerates AD pathologies, impairing learning and memory. Conversely, deletion of UNC5C from netrin-1-depleted mice attenuates AD pathologies and rescues cognitive disorders. Hence,-secretase truncates UNC5C and elevates its neurotoxicity, contributing to AD pathogenesis.

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Chen, G., Kang, S. S., Wang, Z., Ahn, E. H., Xia, Y., Liu, X., … Ye, K. (2021). Netrin-1 receptor UNC5C cleavage by active-secretase enhances neurodegeneration, promoting Alzheimer’s disease pathologies. Science Advances, 7(16). https://doi.org/10.1126/sciadv.abe4499

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