Necroptosis Activation in Alzheimer's Disease

Overview

Journal Nat Neurosci

Date 2017 Aug 1

PMID 28758999

Citations 221

Authors

Antonella Caccamo

Caterina Branca

Ignazio S Piras

Eric Ferreira

Matthew J Huentelman

Winnie S Liang

Ben Readhead

Joel T Dudley

Elizabeth E Spangenberg

Kim N Green

Ramona Belfiore

Wendy Winslow

Salvatore Oddo

Affiliations

Soon will be listed here.

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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