Imaging of tau trans-cellular spreading and seeding in Alzheimer’s disease at single aggregate resolution

• Applicant: Dr. Eleni Dimou
• Subject Area: Biochemistry ; Biophysics ; Cell Biology
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 426806622

Imaging of trans-cellular propagation of tau seeds in Alzheimer’s disease at single aggregate resolutionNeurodegenerative disorders are a major and growing health problem. It is expected that by 2050 the number of Alzheimer’s disease (AD) patients in Europe will increase by more than 85%, so there is an urgent need to create new innovative tools for the early detection of these diseases in order to develop effective therapies. Over the last two decades, a growing number of studies have provided evidence of a common feature of many neurodegenerative diseases: the cell-to-cell propagation of protein aggregates (e.g. Tau in the AD). Therefore, determining the detailed molecular mechanism of trans-cellular propagation of such aggregates is both fundamentally and therapeutically of great importance. However, current conventional biochemical techniques are limited in resolution and sensitivity. Therefore, they cannot be used for the identification and characterization of these low abundance oligomeric species, which are highly heterogeneous in terms of size and structure. The proposed project takes advantage of a wide range of cutting-edge microscopic techniques, including super-resolution methods and aims to adapt them as imaging tools for the detailed characterization of the oligomeric and phosphorylation state of extracellular tau aggregates. The existence of tau in the extracellular space has recently been confirmed in a number of experimental studies and has been directly linked to the elevated levels of free tau in the cerebrospinal fluid during the progression of AD. Most importantly, recent evidence demonstrated that these hyperphosphorylated tau species have a significantly increased capability for the trans-cellular spread of tau aggregation. The systematic analysis and biophysical characterisation of these tau aggregates will provide novel insights into the molecular mechanisms involved in tau secretion and uptake, helping to unravel the mechanistic details of the trans-cellular propagation of tau aggregation in AD.The specific aims of this project are:• The establishment of imaging probes for the determination of the oligomerisation and phosphorylation status of intracellular and extracellular tau with spatial resolution of 20 nm or better.• The characterization of the molecular mechanisms involved in the release of tau into the extracellular space and the determination of the properties of the secreted tau species including their size, structure and seeding capability.• The elucidation of the molecular mechanisms mediating tau uptake from healthy and stressed cells in regard to the size and structure of the aggregates. This study will not only provide crucial insights on the molecular mechanisms governing the biogenesis of protein aggregates, but also bears a significant diagnostic potential for the early detection of AD.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Host: Professor David Klenerman, Ph.D.