Tau Aggregate Structure Determines the Type of Dementia it Causes

Researchers here take what seems to be an important step forward in understanding how aggregates of altered tau protein produce forms of age-related neurodegeneration such as Alzheimer's disease. You might be more familiar with amyloid deposits in the brain in the context of Alzheimer's, but it is becoming clear that tau is probably just as important in this condition, and there are other tauopathies in which it is the dominant cause of cell death and dysfunction. Efforts to safely remove harmful forms of tau are unfortunately lagging behind efforts to clear amyloid, but that should change in the years ahead.

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 to a new study. The research helps explain the diversity of dementias linked to tau protein aggregation, which destroys brain cells of patients with Alzheimer's and other neurodegenerative syndromes. The study also has implications for earlier and more accurate diagnoses of various dementias through definition of the unique forms of tau associated with each. "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. 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."

Researchers had previously determined that tau acts like a prion - an infectious protein that can self-replicate and spread like a virus through the brain. The lab has determined that tau protein in human brain can form many distinct strains, or self-replicating structures, and developed methods to reproduce them in the laboratory. This research led the team to the latest study to test whether these strains might account for different forms of dementia. To make this link, 18 distinct tau aggregate strains were replicated in the lab from human neurodegenerative disease brain samples, or were created from mouse models or other artificial sources. Researchers inoculated the strains into different brain regions of mice and found striking differences among them. Each form created different pathological patterns, recapitulating the variation that occurs in diseases such as Alzheimer's, frontotemporal dementias, and traumatic encephalopathy. The different forms of tau caused pathology that spread at different rates through the brain, and affected specific brain regions. This experiment demonstrated that the structure of pathological tau aggregates alone is sufficient to account for most if not all the variation seen in human neurodegenerative diseases that are linked to this protein. "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. 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."

Link: http://www.utsouthwestern.edu/newsroom/news-releases/year-2016/oct/identifying-tau-strains.html

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