The 'Big Bang' of Alzheimer's: Scientists ID genesis of disease, focus efforts on shape-shifting tau

July 10, 2018 by James Beltran, UT Southwestern Medical Center
Abnormal accumulations of a protein called tau can collect inside neurons, forming tangled threads and eventually harming the synaptic connection between neurons. Credit: National Institute on Aging. UT Southwestern

Scientists have discovered a "Big Bang" of Alzheimer's disease – the precise point at which a healthy protein becomes toxic but has not yet formed deadly tangles in the brain.

A study from UT Southwestern's O'Donnell Brain Institute provides novel insight into the shape-shifting nature of a tau molecule just before it begins sticking to itself to form larger aggregates. The revelation offers a new strategy to detect the devastating disease before it takes hold and has spawned an effort to develop treatments that stabilize tau proteins before they shift shape.

"This is perhaps the biggest finding we have made to date, though it will likely be some time before any benefits materialize in the clinic. This changes much of how we think about the problem," said Dr. Marc Diamond, Director for UT Southwestern's Center for Alzheimer's and Neurodegenerative Diseases and a leading dementia expert credited with determining that tau acts like a prion – an infectious that can self-replicate.

The study published in eLife contradicts the previous belief that an isolated has no distinct shape and is only harmful after it begins to assemble with other tau proteins to form the distinct tangles seen in the brains of Alzheimer's patients.

Scientists made the discovery after extracting tau proteins from human brains and isolating them as single molecules. They found that the harmful form of tau exposes a part of itself that is normally folded inside. This exposed portion causes it to stick to other tau proteins, enabling the formation of tangles that kill neurons.

"We think of this as the Big Bang of tau pathology," said Dr. Diamond, referring to the prevailing scientific theory about the formation of the universe. "This is a way of peering to the very beginning of the disease process. It moves us backward to a very discreet point where we see the appearance of the first molecular change that leads to neurodegeneration in Alzheimer's. This work relied on a close collaboration with my colleague, Dr. Lukasz Joachimiak."

Credit: UT Southwestern

Despite billions of dollars spent on clinical trials through the decades, Alzheimer's disease remains one of the most devastating and baffling diseases in the world, affecting more than 5 million Americans alone.

Dr. Diamond is hopeful the scientific field has turned a corner, noting that identifying the genesis of the disease provides scientists a vital target in diagnosing the condition at its earliest stage, before the symptoms of memory loss and cognitive decline become apparent.

His team's next steps are to develop a simple clinical test that examines a patient's blood or spinal fluid to detect the first biological signs of the abnormal tau protein. But just as important, Dr. Diamond said, efforts are underway to develop a treatment that would make the diagnosis actionable.

He cites a compelling reason for cautious optimism: Tafamidis, a recently approved drug, stabilizes a different shape-shifting protein called transthyretin that causes deadly protein accumulation in the heart, similar to how tau overwhelms the .

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

Dr. Diamond's lab, at the forefront of many notable findings relating to tau, previously determined that tau acts like a prion – an infectious protein that can spread like a virus through the brain. The lab has determined that tau protein in the human brain can form many distinct strains, or self-replicating structures, and developed methods to reproduce them in the laboratory. He said his newest research indicates that a single pathological form of tau protein may have multiple possible shapes, each associated with a different form of dementia.

Explore further: Structure of toxic tau aggregates determines type of dementia, rate of progression

More information: Hilda Mirbaha et al. Inert and seed-competent tau monomers suggest structural origins of aggregation, eLife (2018). DOI: 10.7554/eLife.36584

Related Stories

Structure of toxic tau aggregates determines type of dementia, rate of progression

October 28, 2016
The distinct structures of toxic protein aggregates that form in degenerating brains determine which type of dementia will occur, which regions of brain will be affected, and how quickly the disease will spread, according ...

Abnormal brain protein may contribute to Alzheimer's disease development

September 30, 2016
A recently-recognized pathologic protein in the brain may play a larger role in the development of clinical Alzheimer's disease dementia than previously recognized, according to a study by researchers at Rush University Medical ...

Alzheimer's disease, other conditions linked to prion-like proteins

May 23, 2014
(Medical Xpress)—A new theory about disorders that attack the brain and spinal column has received a significant boost from scientists at Washington University School of Medicine in St. Louis.

Different disease types associated with distinct amyloid-beta prion strains found in Alzheimer's patients

January 9, 2018
An international team of researchers has found different disease type associations with distinct amyloid-beta prion strains in the brains of dead Alzheimer's patients. In their paper published in Proceedings of the National ...

Alzheimer's Tau protein forms toxic complexes with cell membranes

November 22, 2017
The brains of patients with Alzheimer's disease contain characteristic tangles inside neurons. These tangles are formed when a protein called Tau aggregates into twisted fibrils. As a result, the neurons' transport systems ...

Recommended for you

Meditation and music may alter blood markers of cellular aging and Alzheimer's disease

November 13, 2018
A research team led by Dr. Kim Innes, a professor in the West Virginia University School of Public Health, has found that a simple meditation or music listening program may alter certain biomarkers of cellular aging and Alzheimer's ...

Alzheimer's and cardiovascular disease share common genetics in some patients

November 9, 2018
Genetics may predispose some people to both Alzheimer's disease and high levels of blood lipids such as cholesterol, a common feature of cardiovascular disease, according to a new study by an international team of researchers ...

Artificial intelligence predicts Alzheimer's years before diagnosis

November 6, 2018
Artificial intelligence (AI) technology improves the ability of brain imaging to predict Alzheimer's disease, according to a study published in the journal Radiology.

Diabetes medications may reduce Alzheimer's disease severity

November 1, 2018
People with Alzheimer's disease who were treated with diabetes drugs showed considerably fewer markers of the disease—including abnormal microvasculature and disregulated gene expressions—in their brains compared to Alzheimer's ...

Massive study confirms that loneliness increases risk of dementia

October 29, 2018
A new Florida State University College of Medicine study involving data from 12,000 participants collected over 10 years confirms the heavy toll that loneliness can take on your health: It increases your risk of dementia ...

Bioactive compound from the Rhodiola plant improves memory

October 25, 2018
In an ageing society, more people are suffering from memory disorders. The progressive loss of memory severely impairs the quality of life of those affected. So far, no drugs are known to prevent age-related cognitive decline.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.