@article{58592dedbfdc48cb8536d276bc2c7340,
title = "Necroptosis activation in Alzheimer's disease",
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.",
author = "Antonella Caccamo and Caterina Branca and Piras, {Ignazio S.} and Eric Ferreira and Huentelman, {Matthew J.} and Liang, {Winnie S.} and Ben Readhead and Dudley, {Joel T.} and Spangenberg, {Elizabeth E.} and Green, {Kim N.} and Ramona Belfiore and Wendy Winslow and Salvatore Oddo",
note = "Funding Information: 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{\textquoteright}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{\textquoteright}s Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer{\textquoteright}s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer{\textquoteright}s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson{\textquoteright}s Disease Consortium), and the Michael J. Fox Foundation for Parkinson{\textquoteright}s Research.",
year = "2017",
month = sep,
day = "1",
doi = "10.1038/nn.4608",
language = "English",
volume = "20",
pages = "1236--1246",
journal = "Nature Neuroscience",
issn = "1097-6256",
publisher = "Nature Publishing Group",
number = "9",
}