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July 24, 2017

Findings of team led by ASU scientists offer hope for therapies targeting cell loss in the brain, an inevitable and devastating outcome of Alzheimer’s progression

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 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 disease.

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 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 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’s disease (amyotrophic 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 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.

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 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 Oddo, “but everybody agrees that the end result is the neuronal loss. If you can prevent that you may have a beneficial effect.” 

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.

Joe Caspermeyer

Managing editor , Biodesign Institute

480-258-8972

 
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July 24, 2017

USDA awards nearly $1 million to research from W. P. Carey School of Business looking at online marketplaces, scan-based trading

Researchers from Arizona State University’s W. P. Carey School of Business will explore solutions to food waste through two unique research projects funded by nearly $1 million from the USDA’s Agriculture and Food Research Initiative.

Online marketplaces to reduce waste

The first project will test online marketplaces and mobile apps. These emerging sharing-economy companies could help farmers, restaurants, retailers and households manage problems with day-to-day food waste. 

For example, if a farmer has a box of ugly fruits or tomatoes that won’t sell in the supermarket because they’re too big for the grocery-store display, he can use an online platform to let others know he has a surplus of food. Consumers then visit the app or website, select the items they want, and the app coordinates delivery logistics and payment for the farmer.

Lead investigator Tim Richards says the idea is making markets out of what would otherwise be waste. 

“In Arizona and around the country, 18 percent of landfills is food waste, according to the EPA — and that may be a conservative number,” says Richards, the Marvin and June Morrison Chair in Agribusiness at the W. P. Carey School. “If we can figure out a way to better utilize food that would otherwise be wasted, we can minimize what goes into our landfills and more importantly make better use of the water that’s used to irrigate plants, saving 25 percent of our freshwater supply each year.” 

Researchers at ASU are teaming up with Imperfect Foods, a startup delivery company based in San Francisco, to test market theories and demand conditions. In addition, the experiment will use 400 business students at Arizona State University and California Polytechnic State University to measure their use of food waste.

At the conclusion of the two-year research period, investigators hope to be able to answer the following:

  • How will these innovations impact farmers and consumer food prices?
  • How will knowledge and information impact demand uncertainty among food manufacturers, family meal planning and food waste?
  • Are stakeholders in the food supply chain receptive to dealing with collaborative enterprises?

Food Waste: A Market-Based Solution Using Commercial Peer-to-Peer Mutualization Systems won an Agriculture Economics and Rural Communities (AERC) grant totaling $496,589. 

A closer look at scan-based trading

A second ASU research project will put scan-based trading (SBT) under the microscope. SBT is a newer type of contract used by food suppliers and retailers such as Walmart and Target, where the supplier retains ownership of the inventory in stores until the product is scanned at the register for checkout.

Suppliers, such as dairy producers or bakery vendors, are responsible for keeping products in stock, while the retailer provides vendors with valuable shelf space and its employees manage that space. Any loss of product between delivery and checkout is typically the responsibility of the supplier, not the retailer. 

One major problem in SBT is “shrink,” the loss of product between delivery and checkout — anything from expired inventory and broken cartons to theft. This could mean a loss for the supplier under an SBT contract, who may decide to increase wholesale prices to cover its losses. The retailer could then pass that increase along to customers by raising prices, according to lead investigator Elliot Rabinovich.

“We hope to explore the causes of shrink and how to address it. Can suppliers do a better job at managing it? Or do retailers need to have greater sensitivity — regardless of whether they own the inventory or not,” said Rabinovich, a supply chain expert and the John G. and Barbara A. Bebbling Professor of Business at the W. P. Carey School. “It’s not finding out who’s at fault, it’s how do we work together.”

SBT contracts do have benefits, including giving suppliers access to real-time sales information from retail checkouts and the flexibility of replenishing stock in-store without having to go through a distribution center, which traditional contracts often require. 

At the conclusion of the two-year research period, investigators hope to be able to answer the following:

  • How can SBT contracts support the objectives for all involved — retailers, suppliers and the farmers who sell to them?
  • Is there potential to minimize food waste through the supply system by using SBT?
  • How does shrink at SBT stores and non-SBT stores impact wholesale and retail costs?

Scan-Based Trading: Opportunities for Enhancing Supply-Chain Efficiency won an AERC grant totaling $496,407. 

Rebecca Ferriter

Communications Manager , W. P. Carey School of Business

310-871-9041