Process That Changes Tau Protein into Toxic Driver of Alzheimer’s Described in Study

Process That Changes Tau Protein into Toxic Driver of Alzheimer’s Described in Study

The process by which the tau protein is transformed from a healthy cell component into a driver of crippling diseases is described by researchers at UT Southwestern’s O’Donnell Brain Institute.

Their work sheds new light on the underlying mechanism involved in several neurodegenerative disorders, such as Alzheimer’s disease and other tauopathies.

The study, “Inert and seed-competent tau monomers suggest structural origins of aggregation,” was published in the journal eLife.

Two of the main features of Alzheimer’s disease are the formation of so-called “amyloid plaques” and “tau tangles” in the brain. These are characterized by an abnormal accumulation of aggregates of synuclein and tau proteins that are toxic to brain cells, prompting their death.

To date, it’s unclear what happens to tau protein to trigger it forming such toxic aggregates. This has mostly been attributed to its natural instability, which when associated with other disease-related factors could support Alzheimer’s development.

However, findings in this study challenge this hypothesis, and provide evidence that tau proteins undergo a specific transformation to become prone to aggregation.

“We think of this as the ‘Big Bang’ of tau pathology,” Marc Diamond, MD, director for UT Southwestern’s Center for Alzheimer’s and Neurodegenerative Diseases and senior study author, said in a news release. “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.”

In a series of experiments with isolated tau proteins extracted from human brains, the researchers found that the tau protein in its harmful form exposes one part of itself that is normally hidden (folded to its interior). As this small part becomes exposed, it can stick to other tau proteins, allowing the formation of toxic aggregates or tangles.

“This changes much of how we think about the [tau tangles] problem,” Diamond said. “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.”

The researchers believe this discovery opens new possibilities in working to prevent tau protein transformation and stabilize the protein to avoid the shift in structure shape.

Early identification of these exposed versions of the tau protein — possibly evident in blood or spinal fluid samples of people at risk of Alzheimer’s or tauopathies — may also be useful in diagnosing such neurodegenerative disease before symptoms are established. With this in mind, the researchers plan to work to develop a clinical test that might detect the harmful tau protein in patient’s blood or spinal fluid.

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

One comment

  1. DANTE MARCIANI says:

    Interesting finding that open doors to preventive treatments. Perhaps it is relevant that in tau like amyloid-beta, the villains are oligomers, not monomers of in as the case of amyloid insoluble plaque. Yet, from the available data, it seems that both tau and amyloid-beta are partners in crime, aggravating Alzheimer’s disease.

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