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Critical protein shows promise for the treatment of Alzheimer's

August 30, 2016

ASU researcher and colleagues' findings offer insights that may help demystify one of the most shattering human illnesses

The tidal wave approaches. In the coming decades, Alzheimer's disease is projected to exact a devastating economic and emotional toll on society, with patient numbers in the U.S. alone expected to reach 13.5 million by midcentury at a projected cost of more than a trillion dollars.

Salvatore Oddo (left), a researcher at Biodesign Neurodegenerative Disease Research CenterThe Biodesign Neurodegenerative Disease Research Center is a partnership between ASU and Phoenix-based Banner Health. and Arizona State University associate professor, has been investigating the underpinnings of this devastating illness.

In new research appearing in the journal Molecular Psychiatry, Oddo and his colleagues examine a critical protein associated with telltale symptoms of Alzheimer's. They have shown that the protein p62 is associated with the accumulation of plaques formed in the brain from deposits of another crucial protein known as amyloid beta.

The study holds clues for reversing the effects of damaging plaques in the brain by demonstrating for the first time that this protein regulates the degradation, or turnover, of amyloid beta in living systems.

"These exciting finding suggest that compounds aimed at increasing p62 may have beneficial effects for Alzheimer's disease," Oddo said.

The multi-purpose protein p62 has already been associated with the other classic neurological symptoms of Alzheimer's. Known as neurofibrillary tangles, these twisted strands of tau protein form inside dying cells, destroying vital pathways for nutrients.

Unremitting destruction

Alzheimer's disease causes nerve cell death and tissue loss throughout the brain. During the course of the disease, the brain shrinks dramatically, affecting nearly all its functions. Shrinkage of the brain is acute in the cortex, damaging areas critical for thinking, planning and remembering. Atrophy is particularly severe in the hippocampus, an area of the cortex that plays a crucial role in formation of new memories. By contrast, the fluid-filled spaces in the brain known as ventricles grow larger.Alzheimer's is on a rapid and devastating assent, due in part to an aging U.S. population and greater average lifespans. One in three seniors dies with Alzheimer's or a related form of dementia. New cases of the ailment occur every 66 seconds, with the pace accelerating to 1 every 33 seconds by 2050. Environmental factors ranging from diet and exercise to long-term health conditions, including high blood pressure and diabetes, may also play a role.

In addition to the catastrophic effects of Alzheimer's on the lives of patients, the disease places overwhelming stress on immediate caregivers, often leading to depression and, in some cases, economic bankruptcy.

In 2015, 15.9 million family members and friends of those suffering from Alzheimer's and other forms of dementia provided a staggering 18.1 billion hours of unpaid care with an economic value of $221.3 billion.

While commonly described as a disease of old age, early-onset forms can strike in midlife. Further, an increasing body of research suggests the ravaging of the brain caused by the disease actually begins decades before the onset of clinical symptoms.

A clue emerges

The protein p62 is known to perform an array of vital functions in cells. Of particular interest is p62's role in the aggregation and degradation of a pair of proteins long recognized as hallmarks of Alzheimer's disease — amyloid beta and tau.

A virus loaded with the protective protein p62 was infected into mice.

A virus loaded with the protective protein p62 was infected into mice. The green (e, f) and red stains (g, h) show that the virus can infect neurons in the hippocampus and cortex, important regions of the brain implicated in Alzheimer’s disease.

The authors demonstrate, for the first time, that a modified strain of mice generated to display human-like symptoms of Alzheimer's show significant cognitive improvements, including a reversal of spatial memory deficit, when the brain's expression of p62 is restored.

The study further shows that the improvement is associated with reduced levels of amyloid beta and associated plaques in the brain. Finally, the new research describes the mechanism by which p62 activity improves Alzheimer's disease symptoms in mice — by a process known as autophagy. The term refers to the degradation or disassembly of unnecessary or dysfunctional components of cells, a form of biological recycling essential for cellular health.

Reduce, reuse, recycle

Maintenance of human health requires intensive and ongoing cleanup operations. Proteins essential to life processes must be degraded after fulfilling their assigned tasks, which range from providing structural support to cells and tissues to protecting the body from pathogenic foreign invaders. If the body's housekeeping operations are stalled or inefficient, the results can be disastrous.

Previous research has revealed how imbalances between protein production and degradation can lead to accumulations of protein products associated with several deadly neurodegenerative disorders, including frontotemporal lobar degeneration, amyotrophic lateral sclerosis and Alzheimer's disease.

During the process of autophagy, unwanted constituents of cells are isolated and walled off in specialized double-membraned compartments known as autophagosomes. The packaged protein detritus then fuses with lysosomes, organelles in the cell's cytoplasm whose digestive enzymes break down protein components. Recycling is completed when constituent amino acids from degraded proteins become the raw material for new proteins.

Reducing amyloid beta protein in the brain

Microphotographs of the brain show that the presence of p62 in the brain can dramatically reduce the amount of amyloid beta protein (Aβ42) both in the hippocampus (a,b) and cortex (d, e). Amyloid protein is associated with the development of harmful Alzheimer’s disease plaques.

The study observed the behavior of mice genetically bred to lack the p62 protein, resulting in age-dependent cognitive deficits. Earlier observations pointed to the underlying role of p62 in regulating the accumulation of tau protein in the brain. As the authors note, p62 binds strongly to these tau tangles in Alzheimer's, most likely in order to mark them for degradation.

Memory and cognition were assessed through a simple test in which the mice had to mentally recall the locations of submerged platforms in a circular water maze. P62 was introduced to the transgenic mice through a virus specifically designed to carry it into the mouse brain.

Mice received four training trials per day in the water maze for five consecutive days. While all the mice improved over the five-day trials, those expressing p62 performed markedly better, displaying restoration of cognitive skills. The mode of action of p62 appears to be the induction of autophagy and the delivery of amyloid beta to lysosomes for processing and breakdown, thereby reversing the buildup of amyloid beta associated with cognitive impairment.

These data indicate that p62 leads to the induction of autophagy and facilitates the delivery of protein byproducts to lysosomes. Loss of p62 function in Alzheimer's disease, perhaps due to oxidative damage of its promoter, is linked with the accumulation of both plaques and tangles.

The research results open the possibility of restoring neuronal function through the removal of tau and amyloid beta by means of p62-induced autophagy. Future studies should help to further unravel the details of autophagy-lysosomal recycling systems in the onset and progression of Alzheimer's disease.

Top image by Jason Drees/Biodesign Institute

Richard Harth

Science writer , Biodesign Institute at ASU


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Taming Teo's teeming storeroom

Real-life Raiders of the Lost Ark: ASU grads tame Teo's teaming storeroom.
August 30, 2016

ASU grad students energized by challenge of organizing Teotihuacan Research Laboratory's tens of thousands of artifacts

Editor’s note: This is the third in a three-part series on ASU’s archaeology lab in San Juan Teotihuacan, Mexico. Click for the first and second installments. Lab director Michael E. Smith will appear Wednesday in Tempe to talk about new discoveries; find event information at the bottom of this story.

Step into the storerooms of the Teotihuacan Research Laboratory and the first thing you will think of is the government warehouse at the end of “Raiders of the Lost Ark.”

Shelves rise to the ceiling. Row upon row of cardboard and wooden boxes disappear into the gloom. It looks endless. Ranks of shoeboxes and wooden crates are labeled “figurillas,” end scrapers, sherds, fine knives, obsidian, unifacial perforators.

Ask a normal person to organize this in some kind of coherent fashion and he would become physically ill. It’s a "Sorcerer’s Apprentice" task.

Enter Katie Rush and Lisa Gallagher. They are not normal people. They are master’s students in museum studiesRush and Gallagher's museum studies program is part of the School of Human Evolution and Social Change. at Arizona State University, and they spent more than a month this past summer organizing the vast collection of artifacts, which encompass excavations going back to the 1960s at the ancient city of Teotihuacan in Mexico.

Understand we are not talking simply about things like pots, masks and knives, which you might see in a museum. These boxes hold millions of potsherds, flakes of obsidian and the like, things that mean little to laypeople, but which archaeologists can conjure entire worlds out of.

Gallagher and Rush weren’t horrified when they saw the ocean of boxes. To give an idea, no one knows exactly how many boxes are in the collection. A ballpark estimate of 24,000 is the consensus.

“We knew what to expect,” Gallagher said. “I was very excited when I came into the lab and saw all the work that needed to be done. There’s a sense of pride to be able to come here and help organize these collections that mean so much to Mesoamerican researchers.”

“It’s kind of like a library with objects,” Rush said. “In the collectors’ world, you’ve either got too much info or not enough; there’s never a happy medium.”

Video by Ken Fagan/ASU Now

They did a 33-day stint at the lab, which is part of ASU’s School of Human Evolution and Social Change in the College of Liberal Arts and Sciences.

“It’s time-consuming, but it’s not hard,” said Rush. “When you get the flow of things it goes pretty quickly.”

Each researcher cataloged their collection with their own system. What Gallagher and Rush did was create a uniform system for the entire collection. They organized boxes, did data entry and opened containers that hadn’t been opened in decades.

“We’re putting a uniform category on every box, so anyone can walk in the lab and know where it came from,” Gallagher said. “Our goal, when this is all done, is to have a master digitized inventory and have everything be under one uniform catalog.”

Unlike objects in a museum, these artifacts will be moved and handled and unpacked and repacked. It’s not organized for visitors to gawk at; it’s organized for maximum effectiveness for researchers.

For example, there are sample boxes of every type of Teotihuacano pottery: thin orange, gulf fine paste, Metepec. Trading across Mesoamerica was widespread. Researchers from a Mayan dig in southern Mexico might want to visit and see if what they have is from Teotihuacan.

“People want to come and see Teotihuacan pottery looks like,” lab director Michael Smith said. “A lot of people come to consult these.”

“Working with these boxes, it’s not your typical collection,” Gallagher said. “This is a different perspective on collections management. ... It’s designed to be used.”

Smith came to a museum studies class last spring and gave a presentation on Teo and offered two internships to sort out the collection.

“There’s not too many opportunities for students to go out of the country and work in different labs,” Gallagher said. “This is definitely a unique opportunity.”

Rush had done an internship at a museum in Dublin, so she jumped at the chance. She wasn’t familiar with Mesoamerican history and culture before working at the lab.

“It’s very fascinating, and the site is really cool,” she said.

Hear Smith speak in Tempe

What: "New Views of the Ancient City of Teotihuacan" lecture.

When: 6-8 p.m. Wednesday, Aug. 31.

Where: Alumni Lounge (Room 202), Memorial Union, Tempe campus.

Details: Free and open to the public. Find more at the events site.