Cell Death Mechanism Involved in Other Diseases Plays Role in Development of Alzheimer’s, Study Reports

Joana Fernandes, PhD avatar

by Joana Fernandes, PhD |

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A cell death mechanism linked to neuron loss in ALS and stroke also plays a role in neuron loss in Alzheimer’s, a study reports.

The insight could lead to ways to stop neuron death in Alzheimer’s and to the development of therapies.

Scientists have known that the cell death mechanism, necroptosis, plays a role in the development of amyotrophic lateral sclerosis, stroke and other neurodegenerative conditions. But until this Arizona State University study, they did not know it was linked to Alzheimer’s.

The research, “Necroptosis activation in Alzheimer’s disease,” was published in Nature Neuroscience.

“We anticipate that our findings will spur a new area of Alzheimer’s disease research focused on further detailing the role of necroptosis and developing new therapeutic strategies aimed at blocking it,” Dr. Salvatore Oddo, the study’s senior researcher, said in a news release.

Necroptosis causes neurons to burst from the inside out and die. The activation of three proteins —  RIPK1, RIPK3 and MLKL — triggers the damage.

Researchers discovered that a cascade of events links the activation of the proteins to neuron death.

“There is no doubt that the brains of people with Alzheimer’s disease have fewer neurons,” Oddo said. “The brain is much smaller and weighs less; it shrinks because neurons are dying. That has been known for 100 years, but until now, the mechanism wasn’t understood.”

Using human brain tissue samples, the team observed that RIPK1 and RIPK3 bind together to form a structure called a necrosome that kicks off the necroptosis process. This activates the third protein, MLKL, which interferes with the normal activity of cells’ energy-producing mitochondria, killing neurons.

Researchers compared levels of RIPK1 and MLKL with patients’ cognitive health scores. The higher the protein levels, the worse the scores. The cognitive-health yardstick the team used was patients’ scores on the Mini-Mental State Examination.

“In this study, we show for the first time that necroptosis is activated in Alzheimer’s disease, providing a plausible mechanism underlying neuronal loss in this disorder,” said Dr. Winnie Liang, the author of the research.

The team also showed that reducing necrosome activation in mice led to improved neuron health and better performance in memory-related tasks. This suggested that RIPK1, RIPK3 and MLKL could be targets for future therapies.

“One may not agree as to which molecules trigger Alzheimer’s disease, ” Oddo said, “but everybody agrees that the end result is the neuronal loss. If you can prevent that, you may have a beneficial effect.”