1:02 PM
Aug 31, 2017
 |  BC Innovations  |  Targets & Mechanisms

Necroptosis strikes again

Direct evidence of necroptosis in Alzheimer's

Adding to the list of necroptosis-related pathologies, a group from Arizona State University has shown the cell death pathway is activated in Alzheimer’s disease. The data, published last month in Nature Neuroscience, identify potential targets in the pathway and open the door to investigation of whether blocking necroptosis can complement therapeutic strategies aimed at upstream cytotoxic insults.

Necroptosis is a form of programmed cell death that is associated with inflammation and characterized by cell swelling and membrane rupture, in contrast to the DNA fragmentation and cell shrinkage that marks apoptosis. Necroptosis is driven by the activation and phosphorylation of three central signaling proteins: RIPK1, RIPK3 and MLKL.

While DNA fragmentation- and apoptosis-related caspases have been seen in brains from AD patients, the more proximal signs of apoptotic death such as apoptotic bodies and chromatin condensation have not, which suggests another death pathway may be associated with the disease.

Salvatore Oddo, who led the study, told BioCentury that a key goal in the field is to find links between the observed macro changes and cellular markers that could reveal the mechanism.

“The brain is physically smaller in Alzheimer's and that’s well established. The point of this paper was to understand how all these neurons are dying," Oddo told BioCentury. Oddo is an associate professor in the Neurodegenerative Disease Research Center at Arizona State University.

By labeling brain tissue from autopsied AD patients, his team discovered the number of cells expressing necroptosis markers correlated with the degree of brain size reduction and with pathology scores. In addition, blocking necroptosis with a RIPK1 antagonist decreased neuronal death in a mouse model of the disease.

The discovery marks the fourth neurodegenerative disease in which researchers have found necroptosis markers in patient brains, following amyotrophic lateral sclerosis, Niemann-Pick disease and multiple sclerosis. Studies in animal models have suggested the process also may be involved in Huntington's disease and Gaucher’s disease.

Last year, Harvard University's Junying Yuan, published a Science paper showing that RIPK1-mediated necroptosis was pathogenic in ALS.

Denali Therapeutics Inc. gained the rights to Yuan's RIPK1 program when it acquired Incro Pharmaceuticals Corp. last year. Although Denali announced at the time that it had filed a CTA for a Phase I trial in AD in Europe, CEO Ryan Watts declined to disclose the status of the trial or to comment on the new study.

Still, Oddo thinks that RIPK1 is only part of the story, and that other necroptosis proteins would also make attractive...

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