Tau Aggregate Types Predict Dementia Destiny

Observations of cultured cells revealed distinctly patterned tau strains, some of which are shown here in green. After distinct tau strains were inoculated into the brains of mice, unique patterns of pathology were seen to develop. Ultimately, these patterns were linked to specific dementias. [UT Southwestern]

Perhaps we should stop calling them clumps, the toxic aggregates of tau protein that lead to Alzheimer’s disease and other neurodegenerative syndromes. Since “clump” is, by definition, a confused mass, one could get the idea that any tau clump is much like another. Not so. According to a new study, tau clumps have distinct structures, and these structures appear to account for much of dementia’s diversity. Tau clumps, despite their superficial disorder, may bring more clarity than confusion to the study, diagnosis, and treatment of neurodegenerative diseases.

The distinct structures of tau aggregates determine which type of dementia will occur, which regions of brain will be affected, and how quickly the disease will spread. This finding appeared October 27 in the journal Neuron, in an article entitled, “Tau Prion Strains Dictate Patterns of Cell Pathology, Progression Rate, and Regional Vulnerability In Vivo.”

The article describes how special cell systems were used to replicate distinct tau aggregate conformations. These different forms of pathological tau were then inoculated into the brains of mice. Each form created different pathological patterns, recapitulating the variation that occurs in diseases such as Alzheimer's, frontotemporal dementias, and traumatic encephalopathy.

“We … isolated and characterized 18 tau strains in cells based on detailed biochemical and biological criteria,” wrote the article’s authors. “Inoculation of PS19 transgenic tau (P301S) mice with these strains causes strain-specific intracellular pathology in distinct cell types and brain regions, and induces different rates of network propagation.”

In the cell systems, the tau strains alone sufficed to account for diverse neuropathological presentations, which were like those that define human tauopathies.

“In addition to providing a framework to understand why patients develop different types of neurodegeneration, this work has promise for the development of drugs to treat specific neurodegenerative diseases, and for how to accurately diagnose them,” said Marc Diamond, M.D., founding director of the Center for Alzheimer's and Neurodegenerative Diseases, and professor of neurology and neurotherapeutics with the O'Donnell Brain Institute at UT Southwestern Medical Center. “The findings indicate that a one-size-fits-all strategy for therapy may not work, and that we have to approach clinical trials and drug development with an awareness of which forms of tau we are targeting.”

In previous studies, Dr. Diamond’s lab characterized two tau strains that stably maintain unique conformations in vitro and in vivo, but did not determine the relationship of each strain to parameters that discriminate between tauopathies, such as regional vulnerability or rate of spread. In the current study, Dr. Diamond’s lab took a closer look at tau strains and found that the structure of pathological tau aggregates alone is sufficient to account for most, if not all, of the variation seen in human neurodegenerative diseases that are linked with this protein.

Key findings from the current study include the following:

• Tau forms multiple, unique prion strains with distinct biochemical properties.
• Tau strains induce diverse pathological phenotypes in vitro and in vivo.
• Tau strains target different brain regions and propagate pathology at unique rates.

“The challenge for us now is to figure out how to rapidly and efficiently determine the forms of tau that are present in individual patients, and simultaneously, to develop specific therapies,” noted Dr. Diamond. “This work says that it should be possible to predict patterns of disease in patients and responses to therapy based on knowledge of tau aggregate structure.”