New research uncovers a mechanism that causes neurons - shown here - to die in Alzheimer's disease.
Researchers led by Salvatore Oddo, a neuroscientist at Arizona State University-Banner Health in Phoenix, AZ, have discovered a new way in which Alzheimer's disease (AD) affects the brain. The findings pave the way for an entirely new research area, as well as for new drug targets and, hopefully, new therapies.
The study - published in the journal Nature Neuroscience - shows, for the first time, the role that the process of necroptosis plays in the development of Alzheimer's.
The term "necroptosis" describes one of the several ways in which a cell can die.
This type of cell death is a so-called programmed form of necrosis and is caused by three proteins: RIPK1, RIPK3, and MLKL.
Until now, it was known that this type of cell death - where neurons burst and die - occurs in neurodegenerative diseases such as multiple sclerosis and Lou Gehrig' disease.
However, Oddo and team wanted to know if the process is also activated in Alzheimer's and, if so, how the three proteins trigger the process.
Necroptosis identified for the first time in AD
To do so, the researchers analyzed the postmortem human brain samples of several, different cohorts from the Brain and Body Donation Program at the Banner Sun Health Research Institute and Mount Sinai VA Medical Center Brain Bank.
Some of the brain samples had belonged to patients with Alzheimer's disease, and some samples from healthy brains were used as controls.
Using the brain samples, Oddo and colleagues measured the levels of the three proteins that are implicated in necroptosis. They took the measurements from a brain region called the temporal gyrus - an area known to be severely affected by neuronal loss during Alzheimer's.
The measurements indicated that the levels of the proteins RIPK1 and MLKL were higher in AD brains compared with control brains. Given that these proteins are markers for necroptosis, these preliminary findings gave the researchers the first clue that the programmed form of necrosis may indeed occur in AD.
Next, the researchers wanted to see if they could find evidence for the second stage of necroptosis in AD brains.
This second stage consists of a chain reaction between the three proteins. First, RIPK1 binds to RIPK3 and activates it. Second, RIPK3 binds to and activates MLKL, which then goes through a few more biological transformations, causing necroptosis.
Having analyzed the mRNA and the protein levels, the researchers concluded that necroptosis indeed took place in AD brains.
Then, Oddo and colleagues went on to examine the links between the three proteins and the known pathology of AD. Namely, the scientists used a statistical model called "ordinal logistic regression" to analyze the links with the density of the plaque that usually builds inside AD brains.
They also analyzed the potential associations with the so-called Braak staging - a common method used to determine the stage of the disease in Alzheimer's and Parkinson's.
The researchers found that necroptosis was associated with the build-up of the protein tau - a common marker of AD.
Therefore, necroptosis seems to correlate with the degree of disease severity.
However, no correlation was found between necroptosis activation and beta-amyloid plaque - another main characteristic of AD. The absence of such a correlation was puzzling to the researchers.
Further indications of necroptosis
Oddo and team made further discoveries that indicated necroptosis indeed takes place in Alzheimer's.
One such discovery is a negative correlation they found between brain weight and the genetic expression of the protein RIPK1. A loss of brain weight and tissue are further characteristics that signal an advanced stage of AD.
Another finding in the study regards cognitive performance. The researchers found a correlation between the proteins RIPK1 and MLKL and lower scores on a common test of cognitive performance that the patients had taken before they died.
Finally, the researchers wanted to see whether blocking the process of necroptosis would prevent neuronal death and cognitive impairment in a mouse model of AD.
Encouragingly, they found that indeed, inhibiting the protein pathways to prevent necroptosis also reduced the loss of neurons and increased the mice's cognitive performance.
"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," says Winnie Liang, one of the study's co-authors.
The lead author also comments on the significance of the findings, saying:
"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."
Salvatore Oddo, lead researcher