First of its kind study may lead to new era of Alzheimer’s drug discovery and therapeutic targets
Alzheimer’s disease tragically ravages the brains, memories and ultimately, personalities of its victims. Now affecting 5 million Americans, Alzheimer’s disease is the sixth leading cause of death in the U.S., and a cure for Alzheimer’s remains elusive, as the exact biological events that trigger it are still unknown.
In a new study published today, Arizona State University-Banner Health neuroscientist Dr. Salvatore Oddo and his colleagues from Phoenix’s Translational Genomics Research Institute (TGen) — as well as the University of California, Irvine; and Mount Sinai in New York — have identified a new way for brain cells to become fated to die during Alzheimer’s diseases.
The research team has found the first evidence that the activation of a biological pathway called necroptosis, which causes neuronal loss, is closely linked with Alzheimer’s severity, cognitive decline and extreme loss of tissue and brain weight that are all advanced hallmarks of the disease.
“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,” said Dr. Oddo, the lead author of this study, and scientist at the ASU-Banner Neurodegenerative Disease Research Center at the Biodesign Institute and associate professor in the School of Life Sciences.
The findings appear today in the advanced online edition of Nature Neuroscience.
Necroptosis, which causes cells to burst from the inside out and die, is triggered by a triad of proteins. It has been shown to play a central role in multiple sclerosis and Lou Gehrig’ disease (amyotropic lateral sclerosis, or ALS), and now for the first time, also in Alzheimer’s disease.
“There is no doubt that the brains of people with Alzheimer’s disease have fewer neurons,” said Dr. Oddo. “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.”
Links with Alzheimer’s
Necroptosis was first identified as a result of inflammation, a common malady in Alzheimer’s.
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.
Dr. Winnie Liang, TGen assistant professor, director of TGen Scientific Operations and director of TGen’s Collaborative Sequencing Center, said MLKL executes necroptosis to ultimately cause cell death.
“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. Liang, who contributed to the study’s gene expression analyses.
To explore necroptosis, the research team utilized multiple cohorts of human samples obtained from the Brain and Body Donation Program at the Banner Sun Health Research Institute and Mount Sinai VA Medical Center Brain Bank.
First, they measured RIPK1, RIPK3 and MLKL in a specific region of the brain that is typically ravaged by cell loss during the advance of Alzheimer’s disease — the temporal gyrus. 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. Intriguingly, necroptosis did not appear to be linked with the other chief physiological characteristic of Alzheimer’s pathology, beta-amyloid plaque.
Engines of decline
To assess the relationship between necroptotic protein levels and cognitive health, the study 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.
With such experiments not possible in people, the team demonstrated in a mouse model of the disease 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. Compellingly, mice with inhibited activation of necroptosis pathways performed significantly better in tests of spatial memory involving navigation through a water maze.
New understanding, new hope
The study opens a new window on Alzheimer’s research and offers hope for therapies targeting cell loss in the brain, an inevitable and devastating outcome of Alzheimer’s progression.
Oddo stresses that RIPK1, RIPK3 and MLKL are among many potential drug targets, and others will likely follow as the links between necroptosis and Alzheimer’s become clearer. While multiple causes of the disease are likely, understanding more clearly all targets that trigger disease will offer the best hope, since neuronal loss has been found in people more than a decade before any symptoms of dementia.
“One may not agree as to which molecules trigger Alzheimer’s disease” said Dr. Oddo, “but everybody agrees that the end result is neuronal loss. If you can prevent that you may have a beneficial effect.”
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This work was supported by grants from the Arizona Alzheimer’s Consortium and the National Institutes of Health (R01 AG037637) to Salvatore Oddo, and R01 NS083801 and P50 AG016573 to Kim Green.
Data for the RIPK1 causal regulatory gene network were generated from postmortem brain tissue collected through the Mount Sinai VA Medical Center Brain Bank and were provided by Dr. Eric Schadt from Mount Sinai School of Medicine. The computational resources and staff expertise provided by the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai also contributed to the performance of this research.
Paper Title: Evidence for necroptosis activation in Alzheimer’s disease
Antonella Caccamo1, #, Caterina Branca1, #, Ignazio S. Piras2, Eric Ferreira1, Matthew J Huentelman2, Winnie S. Liang2, Ben Readhead3, Joel T. Dudley3, Elizabeth E. Spangenberg4, Kim N. Green4, Wendy Winslow1, and Salvatore Oddo1,5,*
1Arizona State University-Banner Neurodegenerative Disease Research Center at the Biodesign Institute, Arizona State University, Tempe, AZ, 85281, USA.
2Translational Genomics Research Institute, Phoenix, AZ, 85004, USA.
3 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
4Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, 92697, USA.
5School of Life Sciences, Arizona State University, Tempe, Arizona, 85281, USA
Translational Genomics Research Institute (TGen) is a Phoenix, Arizona-based non-profit organization dedicated to conducting groundbreaking research with life changing results. TGen is focused on helping patients with neurological disorders, cancer, diabetes, and infectious diseases, through cutting edge translational research (the process of rapidly moving research towards patient benefit). TGen physicians and scientists work to unravel the genetic components of both common and rare complex diseases in adults and children. Working with collaborators in the scientific and medical communities literally worldwide, TGen makes a substantial contribution to help our patients through efficiency and effectiveness of the translational process. TGen is allied with City of Hope, a world-renowned independent research and cancer and diabetes treatment center. This precision medicine alliance enables both institutes to complement each other in research and patient care, with City of Hope providing a significant clinical setting to advance scientific discoveries made by TGen. For more information, visit: www.tgen.org. Follow TGen on Facebook, LinkedIn and Twitter @TGen.
About the Biodesign Institute at Arizona State University
The Biodesign Institute plays a critical role in advancing the research mission of Arizona State University, a comprehensive metropolitan university that is the second largest in the U.S. The Biodesign Institute embodies the guiding principles of the New American University, as defined by Arizona State University President Michael Crow, specifically, to conduct use-inspired research, fuse intellectual disciplines and value entrepreneurship. The Biodesign Institute at ASU addresses today’s critical global challenges in healthcare, sustainability and security by developing solutions inspired from natural systems, translating solutions into commercially viable products and clinical practices. For more information, go to: www.biodesign.asu.edu
About the Sun City Brain Bank
The Banner Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona is a world leading, community-based resource to advance our understanding of neurodegenerative diseases. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson’s Disease Consortium) and the Michael J. Fox Foundation for Parkinson’s Research.