Hairpin turns ahead: Scientists identify the ‘Big Bang’ of Alzheimer’s

Abnormal accumulations of a protein called tau can collect inside neurons, forming tangled threads and eventually harming the synaptic connections between neurons. Credit: National Institute on Aging.

As a college summer student, Dr. Marc Diamond worked in the lab of Dr. Stanley B. Prusiner, the famed University of California, San Francisco researcher who later won the Nobel Prize for discovering prions, the infectious proteins that cause mad cow disease.

Dr. Diamond’s father, a neurologist, founded and directed a multidisciplinary center for addiction research at UCSF, and two of his uncles were physicians as well. But if you were to assume from this that everything came easily for Dr. Diamond, now Director of UT Southwestern’s Center for Alzheimer’s and Neurodegenerative Diseases, you would be wrong.

After deciding in 2003 to focus on how the brain’s tau proteins might work like prions to cause neurodegenerative diseases such as Alzheimer’s, it took Dr. Diamond seven years to get National Institutes of Health (NIH) funding for his work. “The ideas were very revolutionary at the time, and we needed tremendous amounts of preliminary data to convince reviewers that this could be true,” Dr. Diamond says. Back then, beta-amyloid tangles were the trending Alzheimer’s research topic.

Later, when he was ready to publish his lab’s first work, which reported that assemblies of tau can journey between cells to spread pathology, he spent 18 months getting rejections before it was finally accepted in the Journal of Biological Chemistry in 2009. It is now the most highly cited work from his lab.

These days, things come a bit easier. Dr. Diamond, Professor of Neurology and Neurotherapeutics and Neuroscience and holder of the Distinguished Chair in Basic Brain Injury and Repair, is considered a leading dementia expert, credited with determining that tau acts like an infectious prion (a protein that can self-replicate its disease-causing structure). In 2014, he became the founding Director of the Peter O’Donnell Jr. Brain Institute’s Center for Alzheimer’s and Neurodegenerative Diseases.

The ‘Big Bang’ of Alzheimer’s

Scientists at UT Southwestern Medical Center have discovered the “Big Bang” of Alzheimer’s disease – the precise point at which a healthy tau protein becomes toxic but has not yet formed deadly tangles in the brain.

His lab’s recent study in eLife made headlines in July for uncovering the very beginnings of tau pathology – the precise point at which a healthy tau protein turns toxic, before it has started forming the deadly tangles in the brain that characterize Alzheimer’s and related disorders.

The study provides novel insight into how tau protein molecules change shape: a region that is normally safely tucked inside the tau protein becomes exposed, allowing it to stick to other tau proteins and form toxic aggregates.

“We think of this as the ‘Big Bang’ of tau pathology,” Dr. Diamond says, in a reference to one of astronomy’s major tenets. “It is perhaps the biggest finding we have made to date – although it will likely be some time before any benefits materialize in the clinic. This is a bit like being able to detect the first evidence of a cancer before it becomes metastatic.”

His lab’s research contradicts the previous belief that an isolated tau protein has no distinct shape and is only harmful after it begins to assemble with other tau proteins to form tangles.

A hunger for understanding

Dr. Diamond moved into medical research after earning a history degree from Princeton University.

He says that as a boy growing up in California, “I was always curious about how things worked.” He enjoyed taking apart old watches or building small boats and rockets using improvised parts.

When it was time for college, he wanted a change. “I found science pretty easy. I was more interested in pursuing something that I would never do again, and that would take me out of my comfort zone.”

Dr. Marc Diamond

The detour has helped in his research, he says. As a liberal arts major, Dr. Diamond honed his reading and writing skills – not always strong suits among science types but important for researchers. “I think the skills you learn as a history major are in certain ways much more applicable to actually doing scientific research than studying science in college courses,” he says. “To study history, you must look at a set of facts and construct a narrative that links them together in a coherent story and then communicate these ideas through your writing.

“This is very much what happens when we look at disparate pieces of data and form a research hypothesis. You don’t typically do this when you study molecular biology or chemistry in college – you just learn about topics as they are known at the time.”

But science called. While in college, he spent two summers working with Dr. Prusiner, a Professor of Neurology at UCSF. In 1997, Dr. Prusiner – now Director of UCSF’s Institute for Neurodegenerative Diseases – won the Nobel Prize in Physiology or Medicine for his work isolating prions. He proposed that term in 1982 as a combination of “protein” and “infectious.” At the time, the concept of infectious proteins was considered heretical.

Important & timely work

The work could not be more important – or timely. Alzheimer’s is:

  • Widespread: More than 5 million people in the United States now suffer from Alzheimer’s, a disease that ravages the brain and eventually leads to death.
  • On the rise: By 2050, that number is projected to rise to 14 million, a nearly threefold increase as the population ages, according to the Centers for Disease Control and Prevention (CDC). 
  • Pervasive: Alzheimer’s is the sixth-leading cause of death among U.S. adults and the fifth-leading cause of death for those 65 and older.
  • Devastating: Despite the billions of dollars spent on clinical trials in recent decades, Alzheimer’s remains one of the most devastating and baffling diseases in the world.

After graduating from Princeton in 1987, Dr. Diamond headed to UCSF School of Medicine. “When I got to medical school, I realized I was really interested in how cells functioned in health and disease,” he says. He took a two-year break from medical school as a Howard Hughes Medical Institute Student Research Fellow to work in the UCSF lab of Dr. Keith Yamamoto, who was studying how nuclear receptors sense hormones in the body and regulate transcription. “After working with Keith, I knew I wanted to be a lab scientist first of all.”

Dr. Diamond finished medical school in 1993, then did his internship and residency at UCSF before heading back to Dr. Yamamoto’s lab. He focused on two neurodegenerative diseases – spinal and bulbar muscular atrophy and Huntington’s disease – both caused by mutations that lead to expanded tracts of glutamine in otherwise functional proteins.

“I decided to focus on neurodegenerative diseases because I recognized that they represent the single most mysterious and awful problem in neurology,” Dr. Diamond says.

Once that decision was made, the path to tau research became more clear. Tau, a brain protein that was originally isolated because it is associated with the microtubule network, is implicated in many neurodegenerative diseases, including Alzheimer’s, and accounts for the vast majority of dementia cases. The myriad diseases caused by tau aggregation are called “tauopathies.”

A problem that needs solving

The work could not be more important – or timely.

More than 5 million people in the United States now suffer from Alzheimer’s, a disease that ravages the brain and is eventually fatal. According to the Centers for Disease Control and Prevention (CDC), by 2050, as the population ages, that number is projected to rise to 14 million, a nearly threefold increase.

Despite the billions of dollars spent on clinical trials in recent decades, Alzheimer’s remains one of the most devastating and baffling diseases in the world.

Dr. Diamond hopes his discoveries will help the field turn a corner. Identifying the genesis of the disease provides scientists a target for diagnosing the condition at its earliest stage, before symptoms of memory loss and cognitive decline appear, he says.

His most recent finding came as a surprise, he says.

“The hunt is on to build on this finding and make a treatment that blocks the neurodegeneration process where it begins. If it works, the incidence of Alzheimer’s disease could be substantially reduced. That would be amazing.”

Dr. Marc Diamond

UT Southwestern scientists made the discovery after extracting tau proteins from human brains and isolating them as single molecules. “We were trying to find the smallest unit of infectious tau that would trigger pathology in cells and were using biochemistry to purify smaller and smaller tau assemblies,” Dr. Diamond says. “We anticipated that the smallest unit would be something greater than or equal to three tau molecules, but when we found in our first experiments that a single tau protein seemed to be sufficient to trigger pathology, that was very unexpected.

“We knew this was a paradigm-shifting discovery, and so we spent about three years just doing controls to be sure we weren’t missing larger assemblies during our purification,” he adds.

Dr. Lukasz Joachimiak, Assistant Professor in the Center for Alzheimer’s and Neurodegenerative Diseases and of Biochemistry and an Effie Marie Cain Scholar in Medical Research, was also integrally involved in the research.

Dr. Diamond’s lab has been at the forefront of other notable findings relating to tau.

Through extensive research, Dr. Diamond and his team have discovered that tau aggregates spread throughout the brain much the same way as prions – the infective proteins found in conditions such as mad cow and Creutzfeldt-Jakob disease. However, unlike with prion diseases, which can be transmitted between mammals, the defective proteins present in dementia patients seem to spread only between cells within a single organism.

A toxic form of the tau protein is associated with Alzheimer’s disease.

By creating tau aggregates in the lab and inoculating a generation of mice with the alternatively folded proteins, Dr. Diamond discovered that each tau aggregate spreads through the brain along different, specified pathways and that the journey it takes is determined solely by its unique protein structure. Furthermore, his group has isolated unique structures of tau that correlate with different types of neurodegenerative disease.

These findings predict that the type of dementia a patient will experience can be determined by identifying the unique tau aggregate structures before the patient even has noticeable symptoms. Because of these breakthroughs, the NIH has devoted new funding initiatives to understanding the role of such unique structures. Researchers around the world are racing to identify them and to develop new drugs to target their growth and spread. This represents a much more nuanced and focused approach to neurodegenerative diseases. 

Turning the corner

One of the Diamond lab’s next steps will be to develop a simple clinical test that examines a patient’s blood or spinal fluid to detect the first signs of the abnormal tau protein – and perhaps even the type of tauopathy that could be starting.

The lab is also collaborating with a biotechnology company, United Neuroscience, to develop vaccines that will trigger a patient’s immune system to attack specific tau aggregate structures.

“I have no way of knowing exactly how long it will take to bring this to trials in patients, but our goal is to do so within a three- to five-year timeline,” he says.

Dr. Diamond points to a compelling reason for cautious optimism in the treatment of dementia. At his Center, several discovery projects are underway, including new ways to use vaccines to get the immune system to help clear tau and the development of small molecules that stabilize the “good” form of tau.

Importantly, the FDA recently gave Breakthrough Therapy designation to an experimental drug (tafamidis) for the treatment of patients with transthyretin (TTY) cardiomyopathy, a rare disease associated with heart failure. TTY, a different shape-shifting protein, causes deadly aggregates in the heart, similar to how tau overwhelms the brain.

“The hunt is on to build on this finding and make a treatment that blocks the neurodegeneration process where it begins,” Dr. Diamond says. “If it works, the incidence of Alzheimer’s disease could be substantially reduced. That would be amazing.”