In a new study, researchers have found the first evidence that the activation of a biological pathway called necroptosis causes cells to die. This neuronal loss is closely linked with Alzheimer’s severity, cognitive decline and extreme loss of tissue and brain weight that are all hallmarks of the disease. The findings appear in Nature Neuroscience.
Necroptosis causes cells to burst from the inside out and die and is triggered by a triad of proteins. It has been shown to play a central role in multiple sclerosis and Lou Gehrig’ disease (amyotrophic lateral sclerosis, or ALS), and now for the first time, in Alzheimer’s disease as well. The brain of people with Alzheimer’s is smaller and weighs less due to shrinkage resulting from neuron death. Until now, the mechanism that triggered neuron death was not understood.
Three critical proteins are involved in the initiation of necroptosis, known as RIPK1, RIPK3 and MLKL. The study describes a key event in the process of necroptosis when RIPK1 and RIPK3 form a filamentous structure known as the necrosome. The formation of the necrosome appears to jump-start the process of necroptosis. It activates MLKL, which affects the cell’s mitochondria, eventually leading to cell death.
To explore necroptosis, the research team utilized multiple cohorts of human samples. First they measured RIPK1, RIPK3 and MLKL in the temporal gyrus, a region of the brain that is typically ravaged by cell loss during the advance of Alzheimer’s disease. Results showed that during necroptosis, these markers were increased in the brains of people with Alzheimer’s disease. Next, they identified the molecular cascade of necroptosis activation, with RIPK1 activating RIPK3 by binding with it. This protein complex then binds to and activates MLKL. Analysis of mRNA and protein revealed elevated levels of both RIPK1 and MLKL in the postmortem brain tissues of patients with Alzheimer’s when compared with normal postmortem brains.
Furthermore, they also demonstrated that necroptosis activation correlated with the protein tau. However necroptosis did not appear to be linked with beta-amyloid plaque, which is the other chief physiological characteristic of Alzheimer’s pathology.
The study also revisited the scores of patients whose postmortem brain tissue was evaluated for necroptosis. Results showed a significant association between RIPK1, MLKL and diminished scores on the Mini-Mental State Examination (MMSE), a widely used test measuring cognitive health.
Given the established relationship between necroptosis and Alzheimer’s pathology, including cell loss and attendant cognitive deficit, the study sought to inhibit the process to study the dynamic effects on cell death and memory loss. Since such experiments are not possible in people, the team used a mouse model of the disease that demonstrated that lowering the activation of the necroptosis pathway reduces cell loss and improves performance in memory-related tasks, offering new hope for human therapeutics to halt or reverse the effects of Alzheimer’s.
The results reveal that the inhibition of necroptosis activation through the blockage of RIPK1 prevents cell loss in mice, offering hope for therapies targeting cell loss in the brain, an inevitable and devastating outcome of Alzheimer’s progression.
Paper: “New brain death pathway in Alzheimer’s disease: First of its kind study may lead to new era of Alzheimer’s drug discovery and therapeutic targets.«
Reprinted from materials provided by Arizona State University.