Noncanonical function of an autophagy protein prevents spontaneous Alzheimer’s disease

Heckmann, Bradlee L., Teubner, Brett J. W., Boada-Romero, Emilio, Tummers, Bart, Guy, Clifford, Fitzgerald, Patrick, Mayer, Ulrike, Carding, Simon, Zakharenko, Stanislav S., Wileman, Thomas and Green, Douglas R. (2020) Noncanonical function of an autophagy protein prevents spontaneous Alzheimer’s disease. Science Advances, 6 (33). eabb9036. ISSN 2375-2548

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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.

Item Type: Article
Faculty \ School: Faculty of Science > School of Biological Sciences
Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: LivePure Connector
Date Deposited: 27 Aug 2020 00:00
Last Modified: 18 Sep 2020 23:54
URI: https://ueaeprints.uea.ac.uk/id/eprint/76668
DOI: 10.1126/sciadv.abb9036

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