An international team of scientists have dismantled the belief that Alzheimer's disease and Chronic Traumatic Encephalopathy have identical pathology. Their discovery offers options for improved diagnosis and potential targeted treatments.

CTE has been making headlines across the sports world. Often referred to as the disease of boxers and football players, CTE may develop in a person following multiple blows to the head. The main characteristic of CTE is the abundance of the aggregated insoluble tau protein, which results in the formation of tau tangles in an individual's brain cells.

Large numbers of tau tangles also exist in Alzheimer's disease. Historically, it was believed that CTE and Alzheimer's disease tau tangles were made in the same way. Instead, what the international research team found and is reported in the journal Nature is a much different story.

Using cryogenic electron microscopy (cryo-EM), the researchers examined tau tangles extracted from the brains of an American football player and two professional boxers, all recognized neuropathologically as having suffered from CTE. What they determined is that the fold of the abnormal tau protein in CTE is different from the tau fold in Alzheimer's disease.

The senior author said: "The use of Cryo-EM has allowed us to determine the 3D structure of tau and facilitated our understanding of how it functions and interacts. Understanding these differences will accelerate the discovery of substances that may prevent the formation of abnormal tau in the brain cells of people suffering from either of these two distinct neurodegenerative diseases."

Similar to Alzheimer’s disease, all six brain tau isoforms assemble into filaments in CTE, and residues K274–R379 of three-repeat tau and S305–R379 of four-repeat tau form the ordered core of two identical C-shaped protofilaments.

However, a different conformation of the β-helix region creates a hydrophobic cavity that is absent in tau filaments from the brains of patients with Alzheimer’s disease. This cavity encloses an additional density that is not connected to tau, which suggests that the incorporation of cofactors may have a role in tau aggregation in CTE. Moreover, filaments in CTE have distinct protofilament interfaces to those of Alzheimer’s disease.

Another author said, "These two new discoveries provide more insights into CTE than had previously existed. The information will be incredibly valuable for the development of novel agents to help in diagnosis and therapeutics specifically designed for individuals fighting CTE.

https://medicine.iu.edu/news/2019/03/researchers-discover-hidden-differences-between-pathology-of-cte-and-alzheimers-disease/

https://www.nature.com/articles/s41586-019-1026-5