In the fight against Alzheimer’s, Down syndrome may hold vital clues


October 17, 2018

At first glance, Down syndrome and Alzheimer’s disease, two severe brain abnormalities, may seem to have little in common. Down syndrome is a hereditary disease, the source of which has long been recognized — a triplication of chromosome 21. By contrast, the overwhelming majority of Alzheimer’s cases (more than 95 percent) do not have a clear-cut genetic source. Instead, the disease, which usually becomes clinically apparent late in life, is caused by a perplexing constellation of factors. While these have been the focus of intense study for more than 100 years, few conclusive answers have come to light.

In new research, Antonella Caccamo and her colleagues explore a number of critical factors that appear to link the two illnesses. The current project will use Down syndrom (DS) as a window into the underlying mechanisms that may give rise to Alzheimer’s pathology. Using this complementary approach, her $3.1 million NIH grant will explore the effects of a critical protein complex known as mTOR. Antonella Caccamo's primary research interest is linked to dissecting the molecular mechanisms underlying the pathogenesis of Alzheimer’s disease (AD). Specifically, she uses complementary approaches to study the role of the mammalian target of rapamycin in AD, and to elucidate the link between Down syndrome and AD. Caccamo has 15 years of experience working on AD and a strong track record of productivity with more than 35 peer-reviewed publications. Download Full Image

In the healthy brain, mTOR is involved in a range of essential physiological processes. mTOR is a regulator of protein synthesis and degradation. It plays a critical role in cell growth, longevity and the formation of the cytoskeleton, which provides living cells with their shape and structure, and mTOR is vital to maintaining the proper energy balance in many tissues throughout the body. mTOR is also implicated in synaptic plasticity, neuronal recovery and the retention of memory.

Caccamo is a researcher in the ASU-Banner Neurodegenerative Disease Research Center. Much of her research focuses on investigating Down syndrome molecular alterations in the brain in order to shed new light on Alzheimer’s disease (AD).

“The ultimate goal of my research is to identify novel and clinically translatable targets, thus aiding in the development of new treatments for AD,” Caccamo said.

Learning from mTOR

Disruption of the mTOR pathway has been implicated in diseases including cancer, obesity and cardiovascular disease. Dysregulation of mTOR also plays an important role in diabetes and aging, two known risk factors for Alzheimer’s disease. Irregularities in mTOR functioning are linked to other neurodegenerative diseases and have been shown to give rise to two distinct neuropathologies: depositions in the brain of plaques composed of the protein amyloid beta (Aβ), and accumulations of another protein — known as tau — that aggregates within neuronal cell bodies, forming neurofibrillary tangles.

Plaques and tangles are the classic hallmarks of Alzheimer’s disease. Intriguingly, they also occur in the brains of virtually all patients with Down syndrome, some 60 percent of whom go on to develop Alzheimer’s disease by age 60. Interestingly, APP (amyloid precursor protein), a protein that when cleaved generates beta amyloid (Aβ), the toxic protein that accumulates in AD and DS brains, is located on chromosome 21, the same chromosome that is triplicated in Down syndrome.

Could disruption of the vital mTOR pathway offer clues to the development of plaques and tangles and the onset of dementia in both DS and AD patients? Is mTOR dysregulation also linked with a particular form of cell death known as necroptosis, likewise implicated in AD and DS pathology? Most importantly, can the investigation of the molecular drivers of AD pathology in DS patients provide a new window into the early mechanisms underlying the development of sporadic Alzheimer’s, the form of the disease that commonly strikes aging adults? These are some of the important questions Caccamo’s new study intends to address.

Relentless scourge

Alzheimer’s disease remains the only leading killer lacking any means of treatment, prevention or cure. The disease is pitiless in its systematic destruction of brain functioning, wiping memories clean and robbing the brain of its essential capacities, ultimately resulting in death — typically within eight to 10 years of clinical diagnosis, though in some cases, Alzheimer’s can drag on for as long as 20 years. The emotional toll on patients, caregivers and society is immense and rapidly mounting.

Additionally, the staggering economic burden currently figures in the hundreds of billions of dollars in the U.S. alone and is projected to top $1 trillion by 2050. The need for viable treatments and preventive strategies could not be more acute.

Today, researchers know that the onset of Alzheimer’s begins decades before its telltale signs become apparent. Some have gone so far as to say that while AD is usually thought of as a disease of old age, it may also be associated with adolescence when the early signposts of the disease are planted in the seemingly healthy brain. Many in the field believe that the best hope for arresting the ominous trajectory of the disease lies in identifying causal mechanisms at the earliest stage, and developing effective means of intervention before the brain is irreparably damaged.

Caccamo believes that mTOR dysregulation may be one such early mechanism, giving rise to AD pathology in aging adults as well as DS patients. Research has demonstrated that mTOR is hyperactive in specific brain regions in both AD and DS patients. mTOR hyperactivity is further associated with tau pathology as well as low levels of TSC2, a critical gene product that is believed to keep mTOR hyperactivity in check. Finally, preliminary data from Caccamo’s research indicates that cell loss in DS patients results in part from necroptosis, a unique form of cell suicide linked with dysregulation of mTOR. 

This combination of factors has led to the central hypothesis of the new study: Dysfunction of the TSC2 complex causes an increase in mTOR activity in DS, leading to AD-like neurodegeneration by inducing necroptosis.

Streams and tributaries of Alzheimer’s pathology

Caccamo’s new project, entitled "Identify common mechanisms of neurodegeneration between Alzheimer’s disease and Down syndrome," addresses these issues on several fronts. The first aim of the project is to identify the molecular mechanisms underlying mTOR hyperactivity in DS. Here, the association of dysfunctional TSC2 with mTOR hyperactivity is explored. What might be causing the downregulation of TSC2 leading to mTOR hyperactivity? Three possibilities are experimentally probed: the presence of epigenetic changes in TSC2 and mTOR, alteration of the turnover rate of the TSC2 protein and newly detected proteins that may likewise contribute to destabilizing the delicate TSC2/mTOR axis.

The second aim of the study is to determine the role of hyperactive mTOR in the development of AD-like phenomena in DS. Here, the hypothesis of hyperactive mTOR leading to AD pathologies, particularly Aβ plaques and neurofibrillary tangles, is explored using Ts65Dn mice, a genetic model of Down syndrome. Caccamo’s preliminary results show that mTOR hyperactivity precedes an increase in Aβ and tau levels and degeneration of cholinergic neurons in mice. By subtly increasing or decreasing mTOR signaling, the study will test the effects of reducing mTOR on Aβ and tau levels as well as degeneration of neurons in the mice. Further, increased mTOR levels will be examined to see if such changes increase AD-like pathology and cognitive deficits. Finally, the study will identify additional proteins falling under the regulation of hyperactive mTOR in DS.

Although the death of nerve cells in both Alzheimer’s and DS brains is a well-recognized occurrence associated with impaired cognitive ability, the mechanisms leading to cell death are still not well understood. The third aim of the new study will be to examine how mTOR hyperactivity contributes to neuronal loss. Earlier work by Caccamo and others suggests that a form of programmed cell death known as necroptosis contributes to the neurodegeneration typically observed in AD brains.

The third phase of the new study will investigate the hypothesis that hyperactive mTOR helps set this neurodegeneration process in motion by activating necroptosis pathways in the brain. Systematically modulating mTOR activity and necroptosis signaling in mouse neurons will be used to test this hypothesis. In addition to improving the understanding of the mechanisms leading to cell death in DS and AD, the research will help elucidate possible therapeutic targets for these two tragic afflictions.

Researchers have much to learn from in-depth studies like these, which delve into mTOR’s profound influence on the brain, in sickness and in health. In addition to its relevance in neurodegenerative disease, mTOR’s crucial role in the aging process may shed new light on other foundational issues in neuroscience.

Richard Harth

Science writer, Biodesign Institute at ASU

480-727-0378

 
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Anderson Cooper still believes in journalism

Cooper to Cronkite students: Passion, not tech skills, will be key to careers.
October 17, 2018

The Emmy winner accepts his 2018 Walter Cronkite Award for Excellence in Journalism and speaks of the continuing importance of the field

CNN reporter Anderson Cooper has covered some of the worst humanitarian crises in the world, yet he remains an optimist about mankind and, especially, the role of journalists in telling people's stories — despite current antagonism toward the media.

“The answer to the attacks on reporting is more reporting,” he said. 

“There is truth and there are lies. There are facts and there is fiction, and it is our job to point that out even if it seems at times like no one is listening,” said Cooper, who received the 2018 Walter Cronkite Award for Excellence in Journalism on Wednesday. A journalist for more than 25 years, he has won 13 Emmys and is the anchor of CNN’s “Anderson Cooper’s 360” and a correspondent for “60 Minutes.”

Global poverty is declining and literacy and health are improving, and there is much to be hopeful about, Cooper said at the awards luncheon held by the Walter Cronkite School of Journalism and Mass Communication at Arizona State University.

“The thing that gives me the most hope is the power each of us has to reach out and care for someone else,” he said.

Cooper, who has covered war zones and natural disasters, recalled the many times he has seen strangers helping each other during a crisis. 

“I’ve seen so many acts of bravery and selflessness among others,” he said.

Cooper praised the Cronkite School students and said he’s impressed that they have a clear vision of their journalism careers. After he graduated from college, he wasn’t sure what he wanted to do. He tried to get a job as a broadcast journalist, but when no one would hire him, he set off for Africa.

“If no one would give me a chance, I had to take a chance. I decided to start going to wars.”

Using a fake press pass, he went to Somalia in 1992, during a famine and civil war.

“Until I had been to Somalia, I had never seen starvation up close,” he said, remembering the bodies piled up everywhere. He sat with a couple whose young son had just died, the boy’s legs as thin as the twigs that made up their hut. He was their fourth child to die.

“It was in that moment I found my calling,” he said. “I knew I couldn’t save people's lives, but I could bear witness to their struggles. They weren’t dying in silence.”

Even with all the powerful stories he has told, Cooper still feels like he rarely does justice to the enormity of the moments he has seen.

“You try to capture all that — not just the facts and numbers and names but the sounds and the smells and the silences. 

“You try to find words to convey the horror and humanity you’re surrounded by.

“More often than not you fail because that camera lens is so small.”

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Cronkite School Dean Christopher Callahan (left) and ASU Provost Mark Searle present Anderson Cooper (center) with his Walter Cronkite Award for Excellence in Journalism. Photo by Charlie Leight/ASU Now

Christopher Callahan, the dean of the Cronkite School, thanked Cooper for “speaking truth to power in the great tradition of Walter Cronkite.”

“At a time in our history when journalism, facts and the truth itself are under attack every day, we believe that a free, robust and unfettered press remains the most essential element to the health and the future of our great country, our democracy and our freedom,” Callahan said.

Gabriella Bachara, a senior in the Cronkite School, told the crowd that Cooper is a constant presence on the big TV screen in the First Amendment Forum in the school. 

“I’ve sat in the forum with hundreds of other students watching him break the biggest news stories during my four years here at ASU,” she said.

After the luncheon, Cooper met with students in the Cronkite School on ASU's Downtown Phoenix campus.

Senior journalism major Bryce Newberry asked Cooper how he prepares a show when the news is constantly changing.

“All I do is read stuff all day long,” Cooper said. 

“What I prepare for are contentious interviews. I spend hours looking for transcripts of every interview that person has done over the last six weeks.”

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Walter Cronkite School of Mass Communication students packed the First Amendment Forum to hear Anderson Cooper speak on Wednesday afternoon. Photo by Charlie Leight/ASU Now

That preparation allows him to see their talking points.

“You can arm yourself with facts and you’ll see if somebody said something that’s not true, and you have what is true, you can have that in your arsenal to push back.”

Cooper told the students that they have technical skills he never learned, but that passion will be the key to their careers.

“You all have something that is unique and different, and don’t let somebody in a newsroom who’s been in the profession for 40 years squeeze that out of you and make you sound like everybody else who’s already in the newsroom.”

Top photo: Emmy and Peabody Award-winning broadcast journalist Anderson Cooper speaks after receiving the 2018 Walter Cronkite Award for Excellence in Journalism at the Sheraton Grand Phoenix, on Oct. 17, 2018. He spoke of his adventures and some of the journalists he’s known who have given their lives while telling stories around the world. Photo by Charlie Leight/ASU Now

Mary Beth Faller

reporter , ASU Now

480-727-4503