Abstract

Alzheimer's disease (AD) is characterized by severe neuronal loss; however, the mechanisms by which neurons die remain elusive. Necroptosis, a programmed form of necrosis, is executed by the mixed lineage kinase domain-like (MLKL) protein, which is triggered by receptor-interactive protein kinases (RIPK) 1 and 3. We found that necroptosis was activated in postmortem human AD brains, positively correlated with Braak stage, and inversely correlated with brain weight and cognitive scores. In addition, we found that the set of genes regulated by RIPK1 overlapped significantly with multiple independent AD transcriptomic signatures, indicating that RIPK1 activity could explain a substantial portion of transcriptomic changes in AD. Furthermore, we observed that lowering necroptosis activation reduced cell loss in a mouse model of AD. We anticipate that our findings will spur a new area of research in the AD field focused on developing new therapeutic strategies aimed at blocking its activation.

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Acknowledgements

We thank E. Reiman for discussion and assistance, P. Coleman for kindly providing access to his expressing data set. We thank A. Rodin and A. Tran for contributing to the editing of the manuscript. We thank D. Green for kindly providing the MLKL constructs. We are grateful to the Banner Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona for providing the human tissue. Data for the RIPK1 causal regulatory gene network were generated from postmortem brain tissue collected through the Mount Sinai VA Medical Center Brain Bank and were provided by E. Schadt. The computational resources and staff expertise provided by the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai also contributed to this study. This work was supported by grants from the Arizona Alzheimer's Consortium and the US National Institutes of Health (R01 AG037637) to S.O., and R01 NS083801 and P50 AG016573 to K.N.G. The Brain and Body Donation Program is supported by the US National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson's Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer's Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson's Disease Consortium), and the Michael J. Fox Foundation for Parkinson's Research.

Author information

Author notes

    • Antonella Caccamo
    •  & Caterina Branca

    These authors contributed equally to this work.

Affiliations

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

    • Antonella Caccamo
    • , Caterina Branca
    • , Eric Ferreira
    • , Ramona Belfiore
    • , Wendy Winslow
    •  & Salvatore Oddo
  2. Translational Genomics Research Institute, Phoenix, Arizona, USA.

    • Ignazio S Piras
    • , Matthew J Huentelman
    •  & Winnie S Liang
  3. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Ben Readhead
    •  & Joel T Dudley
  4. Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California, USA.

    • Elizabeth E Spangenberg
    •  & Kim N Green
  5. Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.

    • Ramona Belfiore
  6. School of Life Sciences, Arizona State University, Tempe, Arizona, USA.

    • Salvatore Oddo

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Contributions

A.C. and C.B. designed and performed the experiments and analyzed the data. I.S.P. and M.J.H. performed the statistical analyses. E.F. performed the confocal imaging and quantification. W.S.L. generated the expression data from the microarray analyses used to generate the RIPK1 causal regulatory network. B.R. and J.T.D. generated the RIPK1 causal regulatory network and performed the associated gene set analysis. E.E.S. and K.N.G. performed the experiments on 5xFAD mice. R.B. performed the colocalization experiments described in Supplementary Figure 5. W.W. performed the co-immunoprecipitation experiments. S.O. conceptualized and designed the experiments, analyzed the data, and wrote the manuscript. All of the authors contributed to the preparation of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Salvatore Oddo.

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https://doi.org/10.1038/nn.4608

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