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Author Notes:

kye@emory.edu; zhzhqing1990@163.com

K.Y. conceived the project, designed the experiments, analyzed the data, and wrote the manuscript. G.C., Z.W., and E.H.A. designed and performed most of the experiments and analyzed the data. S.S.K. conducted stereotaxic injection of the viral vectors. Y.X. prepared iPSC-derived neurons. X.L. prepared primary neurons and assisted with in vivo and in vitro experiments. I.M.S. and F.P.M. provided the AAV-AEP C189S viral vectors. Z.Z. assisted with data analysis and interpretation and critically read the manuscript.

The authors declare that they have no competing interests.

Subjects:

Research Funding:

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
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • AMYLOID PRECURSOR PROTEIN
  • SURVIVAL FACTOR
  • RARE MUTATION
  • CELL-DEATH
  • IN-VITRO
  • PIKE-L
  • BETA
  • PATHOGENESIS
  • MECHANISM
  • LEGUMAIN

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

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Journal Title:

SCIENCE ADVANCES

Volume:

Volume 7, Number 16

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Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/).
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