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Heckmann BL, Teubner BJW, Boada-Romero E, et al. Noncanonical function of an autophagy protein prevents spontaneous Alzheimer's disease. Sci Adv. 2020;6(33):eabb9036doi: 10.1126/sciadv.abb9036.
Heckmann, B. L., Teubner, B. J. W., Boada-Romero, E., Tummers, B., Guy, C., Fitzgerald, P., Mayer, U., Carding, S., Zakharenko, S. S., Wileman, T., & Green, D. R. (2020). Noncanonical function of an autophagy protein prevents spontaneous Alzheimer's disease. Science advances, 6(33), eabb9036. https://doi.org/10.1126/sciadv.abb9036
Heckmann, Bradlee L, et al. "Noncanonical function of an autophagy protein prevents spontaneous Alzheimer's disease." Science advances vol. 6,33 (2020): eabb9036. doi: https://doi.org/10.1126/sciadv.abb9036
Heckmann BL, Teubner BJW, Boada-Romero E, Tummers B, Guy C, Fitzgerald P, Mayer U, Carding S, Zakharenko SS, Wileman T, Green DR. Noncanonical function of an autophagy protein prevents spontaneous Alzheimer's disease. Sci Adv. 2020 Aug 14;6(33):eabb9036. doi: 10.1126/sciadv.abb9036. eCollection 2020 Aug. PMID: 32851186; PMCID: PMC7428329.
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Sci Adv. 2020 Aug 14;6(33):eabb9036. doi: 10.1126/sciadv.abb9036. eCollection 2020 Aug.

Noncanonical function of an autophagy protein prevents spontaneous Alzheimer's disease.

Science advances

Bradlee L Heckmann, Brett J W Teubner, Emilio Boada-Romero, Bart Tummers, Clifford Guy, Patrick Fitzgerald, Ulrike Mayer, Simon Carding, Stanislav S Zakharenko, Thomas Wileman, Douglas R Green

Affiliations

  1. Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  2. Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  3. School of Biological Sciences, University of East Anglia, Norwich, Norfolk, UK.
  4. Quadram Institute of Bioscience, Norwich, Norfolk, UK.
  5. Norwich Medical School, University of East Anglia, Norwich, Norfolk, UK.

PMID: 32851186 PMCID: PMC7428329 DOI: 10.1126/sciadv.abb9036

Abstract

Noncanonical functions of autophagy proteins have been implicated in neurodegenerative conditions, including Alzheimer's disease (AD). The WD domain of the autophagy protein Atg16L is dispensable for canonical autophagy but required for its noncanonical functions. Two-year-old mice lacking this domain presented with robust β-amyloid (Aβ) pathology, tau hyperphosphorylation, reactive microgliosis, pervasive neurodegeneration, and severe behavioral and memory deficiencies, consistent with human disease. Mechanistically, we found this WD domain was required for the recycling of Aβ receptors in primary microglia. Pharmacologic suppression of neuroinflammation reversed established memory impairment and markers of disease pathology in this novel AD model. Therefore, loss of the Atg16L WD domain drives spontaneous AD in mice, and inhibition of neuroinflammation is a potential therapeutic approach for treating neurodegeneration and memory loss. A decline in expression of ATG16L in the brains of human patients with AD suggests the possibility that a similar mechanism may contribute in human disease.

Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

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