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RETRACTED ARTICLE: p62 improves AD-like pathology by increasing autophagy

Molecular Psychiatry volume 22, pages 865–873 (2017)Cite this article

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A Retraction to this article was published on 11 August 2020

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Abstract

The multifunctional protein p62 is associated with neuropathological inclusions in several neurodegenerative disorders, including frontotemporal lobar degeneration, amyotrophic lateral sclerosis and Alzheimer’s disease (AD). Strong evidence shows that in AD, p62 immunoreactivity is associated with neurofibrillary tangles and is involved in tau degradation. However, it remains to be determined whether p62 also plays a role in regulating amyloid-β (Aβ) aggregation and degradation. Using a gene therapy approach, here we show that increasing brain p62 expression rescues cognitive deficits in APP/PS1 mice, a widely used animal model of AD. The cognitive improvement was associated with a decrease in Aβ levels and plaque load. Using complementary genetic and pharmacologic approaches, we found that the p62-mediated changes in Aβ were due to an increase in autophagy. To this end, we showed that removing the LC3-interacting region of p62, which facilitates p62-mediated selective autophagy, or blocking autophagy with a pharmacological inhibitor, was sufficient to prevent the decrease in Aβ. Overall, we believe these data provide the first direct in vivo evidence showing that p62 regulates Aβ turnover.

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Acknowledgements

We thank Dr Zhu, University of Kentucky, for donating the p62ΔLIR plasmid and Dr Wei Ding, Capital Medical University, China, for donating the wild-type and p62ΔUBA plasmids. This work was supported by grants from the Arizona Alzheimer’s Consortium and the National Institutes of Health (R01 AG037637) to SO.

Author contributions

AC designed and performed the experiments and analyzed the data. EF performed the in vitro experiments and edited the manuscript. CB performed the proteasome experiments and edited the manuscript. SO designed the experiments, analyzed the data and wrote the manuscript.

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Authors and Affiliations

  1. The Arizona State University-Banner Neurodegenerative Disease Research Center, Biodesign Institute at Arizona State University, Tempe, AZ, USA

    A Caccamo, E Ferreira, C Branca & S Oddo

  2. School of Life Sciences, Arizona State University, Tempe, AZ, USA

    S Oddo

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  1. A Caccamo
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Correspondence to S Oddo.

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Caccamo, A., Ferreira, E., Branca, C. et al. RETRACTED ARTICLE: p62 improves AD-like pathology by increasing autophagy. Mol Psychiatry 22, 865–873 (2017). https://doi.org/10.1038/mp.2016.139

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