The LMB Director, Jan Löwe, recently ran an internal video competition in which staff and students could submit ideas for new films about life and science at the LMB. Four ideas were selected as winning entries. One of these, “The tale of tangled tau in Alzheimer’s disease” is focused on the work of Michel Goedert’s and Sjors Scheres’ groups on the structures of tau filaments in Alzheimer’s disease and other neurodegenerative diseases. It is being released to mark World Alzheimer’s Month.
The LMB has been at the forefront of research into Alzheimer’s disease for several decades, with a long line of important discoveries stretching back to the late 1980s when the protein tau was first shown to be an integral component of the neurofibrillary lesions characteristic of Alzheimer’s disease. One of the core ideas of the research done at the LMB is that biological processes can be better understood through the study of the molecules that drive them. Therefore, one of the long-term aims of Michel’s group has been to determine high-resolution structures of tau filaments from the brains of patients with Alzheimer’s disease and other diseases associated with abnormal tau assemblies.
The collaboration between Michel and Sjors started over tea in the LMB canteen where Tony Crowther, a former, now Emeritus, Group Leader, showed Sjors pictures of tau filaments he had taken many years earlier. With recent improvements in electron cryo-microscopy and development of new software that could handle helical samples by Shaoda He in Sjors’ group, they decided to work together to solve the atomic structures of such filaments.
This led to the most recent run of discoveries, starting with the atomic structure of tau filaments from Alzheimer’s disease in 2017. Since then, the team has determined the precise folds made by tau in filaments from three further neurodegenerative diseases: the frontotemporal dementia Pick’s disease; chronic traumatic encephalopathy, a disease associated with repetitive head trauma; and the movement and dementia disorder corticobasal degeneration.
This work revealed that each disease is characterised by a different tau filament structure and that patients with the same disease have the same filament structure. This suggests that there is an intimate relationship between the precise structure that tau forms and the associated disease, which has important medical implications.
Michel: “The most important benefit to emerge from this new work is the possibility to develop specific ligands for early diagnosis of tau proteinopathies. In the longer run, we’d also like to understand the mechanisms that underlie the surprising diversity of tau filament structures found in human brain.”
Sjors: “With a better understanding, at the molecular level, of how tau forms these filaments, and which other molecules may play a role in this too, we may even be able to develop therapeutics that prevent or even reverse filament formation.”
Benjamin Falcon: “We also found that the tau filaments in two of the diseases contain additional molecules hidden within them. We now think it’s possible that these molecules themselves determine which tau filament structure forms and then which disease the patient goes on to develop.”
Previous Insights on Research
First atomic structures of Tau filaments from Alzheimer’s disease brain
Tau filament structures differ between neurodegenerative diseases
New tau structures may benefit diagnosis and treatment of head injury-associated neurodegeneration
A novel tau fold in the neurodegenerative disease corticobasal degeneration