UVA solves mysteries about leading biomarker for Alzheimer’s disease

Discovery advances battle against disease that strikes 1 in 9 people over 65

In Summary:

• UVA scientists have mapped out how a toxic protein spreads through the brain in Alzheimer’s disease.

• Findings explain what triggers the protein’s accumulation and how it harms nerve cells called neurons.

• Research advances efforts to develop blood tests to detect Alzheimer’s at its earliest stages — long before symptoms appear.

CHARLOTTESVILLE — In a press release from the University of Virginia, neuroscientists have revealed how a toxic form of tau protein spreads through the brain as the disease progresses, what provokes its accumulation and how it harms nerve cells called neurons. Scientists may be able to leverage these findings to develop new Alzheimer’s treatments that prevent or delay symptom onset, or slow disease progression once symptoms develop, the release said.

Tau protein is notorious for forming tangles in the brains of people with Alzheimer’s disease and several other neurodegenerative disorders, and for helping to cause cognitive decline associated with those diseases, said the University of Virginia Medical Center in the release.

UVA’s new research also advances efforts to develop blood tests to detect Alzheimer’s at its earliest stages, when it is, in principle, most amenable to treatment.

The researchers found that antibodies used in blood tests for measuring this toxic, chemically modified form of tau, tau_pT217, can easily be fooled into detecting other proteins, which compromises test accuracy. Fortunately, they also showed how this problem can be avoided, the release said.

The new research from UVA’s George Bloom and collaborators is the most comprehensive examination yet of where and how tau_pT217 accumulates in the brain, the release said. The results provide vital insights into the development of Alzheimer’s and possibly other neurological conditions called “non-Alzheimer’s tauopathies,” which include Parkinson’s disease and chronic traumatic encephalopathy.

“The past few years have witnessed exciting advances in early Alzheimer’s detection by measuring the amount of tau_pT217 in blood or cerebrospinal fluid, but until now almost nothing has been learned about what causes this type of tau to form in the brain or how it affects neuron health,” said Bloom, of UVA’s Departments of Biology, Cell Biology and Neuroscience, as well as the UVA Brain Institute, the Virginia Alzheimer’s Disease Center and UVA’s Program in Fundamental Neuroscience. “Knowing what provokes tau_pT217 to build up in the brain and how it harms neurons provides new openings for therapeutic intervention.”

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Understanding Alzheimer’s disease

Tau plays important roles in the healthy brain, where, among other things, it helps build and maintain the “microtubules” that serve as highways for transporting important materials within the neurons that form the brain’s circuitry. But in people with Alzheimer’s, tau becomes chemically modified and misshapen in ways that prevent its normal functioning and make it toxic, the release said. This eventually leads to two phenomena that account for cognitive decline in Alzheimer’s: destruction of neuronal circuitry and neuron death.

Why this occurs has been only partially understood, but UVA’s new research offers more answers. For example, the researchers found that they could trigger tau_pT217 buildup inside cultured neurons by exposing them to clusters, or oligomers, of tau, which are known to accumulate in the Alzheimer’s brain and have long been suspected as a harmful contributor to the disease, the release said. They also found that the chemical modification that converts normal tau into tau_pT217 dramatically decreases tau’s ability to stick to microtubules, which in turn may make it easier for the tau to form toxic oligomers.

“In terms of immediate clinical value, we hope that our findings about the challenge of antibody specificity for measuring tau_pT217 in blood will quickly resonate with companies that are striving to develop commercially available tests to identify Alzheimer’s patients years before symptoms become evident,” Bloom said. “Because massive irreversible brain damage has already occurred by symptom onset, accurate early diagnosis will be crucial for development of drugs that effectively combat Alzheimer’s.”

That’s just one example of the practical insights generated by UVA’s research that will benefit the efforts to better diagnose and treat Alzheimer’s, the release said.

“Alzheimer’s disease reflects a multi-dimensional breakdown of normal brain cells, so there is nothing simple about it,” Bloom said. “Focusing research on the earliest processes that convert normal brains into Alzheimer’s brains, though, provides the best hope for eventually conquering this terrible disease.”

Findings published

The researchers have published their findings in the scientific journal Alzheimer’s & Dementia. The first author of the paper is Binita Rajbanshi, a recently graduated pharmacology PhD student. The other team members were Anuj Guruacharya, James Mandell and Bloom. The scientists reported that they have no financial interests in the work. Research was supported by The Owens Family Foundation, the Cure Alzheimer’s Fund, the Rick Sharp Alzheimer's Foundation, the National Institutes of Health and Webb and Tate Wilson.

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Reporter Monique Calello can be reached at mcalello@newsleader.com. Story ideas are always welcome. Please support local journalism and subscribe to us at newsleader.com.

This article originally appeared on Staunton News Leader: UVA solves mysteries about leading biomarker for Alzheimer’s disease