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

• Type of Material: Article
• Authors: Guiqin Chen, Emory University; Seong Kang, Emory University; Zhihao Wang, Emory University; Eun Hee Ahn, Emory University; Yiyuan Xia, Emory University; Xia Liu, Emory University; Ivette M. Sandoval, Barrow Neurological Institute; Fredric P. Manfredsson, Barrow Neurological Institute; Zhaohui Zhang, Wuhan University; Keqiang Ye, Emory University
• Language: English
• Date: 2021-04-01
• Publisher: AMER ASSOC ADVANCEMENT SCIENCE
• Publication Version: Final Published Version
• Copyright Statement: © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1126/sciadv.abe4499
• Title of Journal or Parent Work: SCIENCE ADVANCES
• Volume: 7
• Issue: 16
• Grant/Funding Information: This work is supported by a grant from the National Institutes of Health (RF1, AG051538) to K.Y. and the State Key Program of the National Natural Science Foundation of China (no. 81671051) to Z.Z. This study was supported in part by the Rodent Behavioral Core (RBC), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities. We thank ADRC at Emory University for human patients with AD and HC samples (P30 AG066511). Additional support was provided by the Viral Vector Core of the Emory Neuroscience NINDS Core Facilities (P30NS055077). Further support was provided by the Georgia Clinical and Translational Science Alliance of the National Institutes of Health under Award Number UL1TR002378.
• Keywords: Science & Technology - Other Topics; BETA; IN-VITRO; MECHANISM; Science & Technology; PATHOGENESIS; AMYLOID PRECURSOR PROTEIN; RARE MUTATION; PIKE-L; SURVIVAL FACTOR; LEGUMAIN; CELL-DEATH; Multidisciplinary Sciences
• Research Categories: Biology, Neuroscience; Health Sciences, Pathology; Biology, Cell

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.