Programmable necroptosis
How brain cells die in Alzheimer's disease
Anna Kerman, XX2 century, based on the materials of MedicalNewsToday: Alzheimer's: New brain cell loss mechanism uncovered
The results of a new study may change the current approach to the treatment of Alzheimer's disease, as scientists have discovered another factor in the death of brain cells.
Salvatore Oddo, a neuroscientist at Arizona State University and the nonprofit Banner Health healthcare system in Phoenix, Arizona, led a study that found another type of Alzheimer's disease (AD) effect on the brain. This opens the way to a new era of research and, hopefully, to new methods of treatment.
The results of the study are published in the journal Nature Neuroscience (Caccamo et al., Necroptosis activation in Alzheimer's disease). During the work, it was shown for the first time what role the process of necroptosis plays in the development of Alzheimer's.
The term "necroptosis" means one of the variants of cell death. The programmed form of necroptosis is caused by three proteins: RIPK1, RIPK3 and MLKL.
Until today, it was known that this type of cell death – when neurons burst and die – occurs in neurodegenerative diseases such as multiple sclerosis and Charcot's disease (amyotrophic lateral sclerosis, in English–speaking countries - Lou Gehrig's disease).
Oddo and his team decided to test whether this process occurs in Alzheimer's disease, and if so, how the proteins mentioned above trigger it. To do this, the researchers studied postmortem samples of human brain tissue. Some samples belonged to patients with Alzheimer's disease, while others (healthy) were used as control.
Oddo and his colleagues measured the level of three proteins involved in necroptosis – measurements were carried out in the temporal gyrus, where Alzheimer's kills especially many neurons.
The work showed that in the samples of patients with Alzheimer's disease, the level of RIPK1 and MLKL proteins is higher than in the control ones. Since these proteins are markers of necroptosis, these results showed that in Alzheimer's disease, the process of programmed necroptosis is really underway.
Next, the researchers had to find out if there was evidence of the second stage of necroptosis: a chain reaction of three proteins. At this stage, RIPK1 binds to RIPK3 and activates it, then RIPK3 binds to MLKL and, in turn, activates it, and MLKL causes necroptosis. After analyzing the concentrations of microRNA and protein, the researchers confirmed the presence of necroptosis.
Then Oddo and his colleagues studied the relationship between the three proteins and the density of plaques accumulating in the brain. It turned out that necroptosis is associated with the accumulation of tau protein, a well-known marker of Alzheimer's disease. Therefore, it seems that necroptosis correlates with the severity of the disease.
However, to the surprise of the researchers, there was no connection between necroptosis and beta-amyloid plaques (another of the main signs of Alzheimer's disease).
The researchers also found a correlation between the levels of RIPK1 and MLKL proteins and low scores in cognitive tests performed by patients before death.
The researchers then tested in an experiment on mice with an Alzheimer's disease model how blocking necroptosis would affect the state of neurons and cognitive activity. Scientists found that blocking proteins that cause necroptosis reduced the loss of neurons and improved the cognitive abilities of mice.
"In this study, we showed for the first time that necroptosis occurs in Alzheimer's disease, which looks like a reliable mechanism underlying the death of neurons in this disease," says study co-author Winnie Liang.
The lead author of the paper also commented on the significance of the discovery: "We expect that our results will open up a new field of Alzheimer's disease research, where much attention will be paid to the role of necroptosis and the development of new strategies to block it."
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26.07.2017