Solid-State NMR Characterization of a PET Ligand Binding Sites in AD Tau Fibrils

Aggregation of the tau protein into fibrils is a key feature of Alzheimer's disease (AD) and many other neurodegenerative disorders. Developing small molecules that bind these tau fibrils is important for the diagnosis and treatment of tauopathies. This thesis revolves around a study on the binding sites of a positron emission tomography (PET) ligand, PI-2620, to a recombinant tau construct that adopts the C-shaped AD fold. Using solid state NMR experiments in combination with other techniques such as Transmission Electron microscopy (TEM) as well as docking simulations allowed a better understanding of the binding sites of this PET agent. Specifically, 13C-19F REDOR experiments were used to identify nearby residues to the ligand. PI-2620 was found to bind two primary sites within the C-shaped structure. The docking simulations allowed the proposition of several possible binding poses. Additional 2D NMR experiments suggest that PI-2620 alters the protofilament interfaces. The stoichiometry of PI-2620 binding to tau fibrils was determined to be approximately 20 mol%, with varying degrees of ligand mobility. These findings offer insights into the interaction of this PET tracer with tau fibrils and have implications for the design of improved imaging agents.

Name thesis:degree_name

Master

Department dc:contributor.department

Massachusetts Institute of Technology. Department of Chemistry

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2025

Author dc:creator

• Angehrn Rodas, Frida Nicole

Advisor dc:contributor.advisor

• Hong, Mei

Statement dc:rights

• In Copyright - Educational Use Permitted
• Copyright retained by author(s)

Licence dc:rights.uri

• https://rightsstatements.org/page/InC-EDU/1.0/

Handle dc:identifier.uri

https://hdl.handle.net/1721.1/162319

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/162319