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Shape and cell type matter for the spread of tau tangles in mouse brain

The spread of tau tangles in the brain, one of the hallmarks of Alzheimer’s disease, depends on the shape of long structures, called tau protein fibrils, rather than the specific variations of tau protein that form the tau fibrillar tangles, according to a study in mice. The findings, published in Nature Communications and funded in part by NIA, provide important insights into how tau tangles spread in the brain for various progressive brain diseases.

Atoms of the tau protein fragment are represented as red and blue and white spheres grouped together.
Tau protein fragment

In Alzheimer’s disease and other progressive brain diseases, abnormal levels of the protein tau clump together to form fibrous tangles. These tau tangles collect and form distinct patterns that disrupt how the cells in the brain function. Researchers know that these different tau patterns are linked to a patient’s symptoms, but how they form and spread in the brain is not well understood.

In progressive brain diseases, six different types of tau proteins combine to form tau fibrils called tau strains. Each tau strain has a unique shape that creates specific cluster patterns in various cells of the brain.

To study how the different tau strains spread in the brain, a team led by researchers at the University of Pennsylvania first created a novel mouse model with the same tau protein types found in the human brain. Using the new model, the researchers injected each tau strain, isolated from different brain disorders, and observed the spread of tau pathology through the mouse brain, as expected in disease-specific patterns. To the researcher’s surprise, the types of proteins within each strain did not determine how widely the tau tangles spread. Instead, the researchers discovered that the overall shape of each tau strain appeared to drive the spread of disease throughout the brain.

In addition, each tau strain is likely maintained and controlled by different cell types in the brain. According to the study, some tau strains are found mainly in glial cells, which are protective cells that surround nerve cells. Other tau strains are more abundant within the nerve cells. However, it is not understood how the conditions inside the different brain cell types lead to the formation of the various tau strains in progressive brain diseases.

Additional research is needed to better understand what causes the normal tau proteins to form the different disease tau strains, and how the different cell environments contribute to these diseases.

This research was funded in part by NIA grants P30AG10124 and P01AG17586.

These activities relate to NIA’s AD+ADRD Research Implementation Milestone 2.A, “Create new research programs that use data-driven, systems-based approaches to integrate the study of fundamental biology of aging with neurobiology of aging and research on neurodegeneration, AD and AD-related dementias to better understand the mechanism(s) of vulnerability and resilience in AD across all levels of biologic complexity (from cellular to population level) and to gain a deeper understanding of the complex biology and integrative physiology of healthy and pathologic brain aging.”

Reference: He Z, et al. Transmission of tauopathy strains is independent of their isoform composition. Nature Communications. 2020;11(1):7. doi: 10.1038/s41467-019-13787-x.