Pathology Differences Distinguish CTE from Azheimer's Disease

Neurological disease researchers have found an important difference that distinguishes the molecular pathology of Chronic Traumatic Encephalopathy (CTE) from that of Alzheimer's disease (AD).

CTE is a neurodegenerative tauopathy - a pathological aggregation of tau protein in neurofibrillary or gliofibrillary tangles in the brain - that is associated with repetitive head impacts or exposure to blast waves. It was described first as "punch-drunk syndrome" and dementia pugilistica in retired boxers, but has since been identified in former participants of other contact sports, ex-military personnel, and after physical abuse. No disease-modifying therapies currently exist, and diagnosis requires an autopsy. In AD, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport system.

Investigators at Indiana University School of Medicine (Indianapolis, USA) used cryo-electron microscopy (cryo-EM) to demonstrate a fundamental difference between the tau tangles of CTE and those of AD. Cryo-EM is an analytical technique that provides near-atomic structural resolution without requirements for crystallization or limits on molecular size and complexity imposed by the other techniques. Cryo-EM allows the observation of specimens that have not been stained or fixed in any way, showing them in their native environment while integrating multiple images to form a three-dimensional model of the sample.

The investigators determined the structures of tau filaments from the brains of three individuals with CTE at resolutions down to 2.3 Angstroms, using cryo-electron microscopy. They showed that filament structures were identical in the three cases but were distinct from those of Alzheimer’s and Pick’s diseases, and from those formed in vitro. In CTE, a different conformation of the beta-helix region created a hydrophobic cavity that was absent in tau filaments from the brains of patients with Alzheimer’s disease. This cavity enclosed an additional density that was not connected to tau, which suggested that the incorporation of cofactors may have a role in tau aggregation in CTE. The discovery of the difference between pathogenic tau of CTE and that of AD offers options for improved diagnosis and potential targeted treatments.

Contributing author Dr. Ruben Vidal, professor in the of pathology and laboratory medicine at Indiana University School of Medicine, 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."

The cryo-EM study was published in the March 20, 2019, online edition of the journal Nature.

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Indiana University School of Medicine