Tokyo, Japan – Researchers from Tokyo Metropolitan University have applied ideas from polymer physics to illuminate the mechanism behind a key pathology in Alzheimer's disease, the formation of fibrils of tau proteins. They showed that fibril formation is preceded by the birth of large protein clusters, mirroring the crystallization of polymers. Crucially, dissolving these clusters helped to prevent fibrils forming in solution. Their work signals a paradigm shift for the development of treatments for neurodegenerative diseases.
Alzheimer's disease (AD) continues to present an immense challenge to scientists, both in understanding its progression and developing effective treatments. With populations aging worldwide, the stakes couldn't be higher. Most approaches have been through the lens of pharmacology and medical science; given the sheer complexity of the disease, adjacent disciplines have become increasingly important in presenting fresh research directions and insights.
Now, a team led by Professor Rei Kurita from Tokyo Metropolitan University have used approaches based on polymer physics to understand one of the key pathologies of AD, the formation of fibrils of the tau protein. They were inspired by the hierarchical process by which polymers, long chain-like molecules, form well-ordered crystals. Instead of individual strands joining onto crystals in a step-by-step fashion, many polymers create intermediate, "precursor" structures before the rearrangements required to form crystals. Applying these ideas to the human tau protein in solution, they were able to confirm that the birth of fibrils (or fibrillization) is preceded by the formation of a similar precursor structure, a loose clustering of tau protein with dimensions of tens of nanometers. They were able to confirm these structures using independent techniques, such as small angle X-ray scattering and fluorescence-based methods.
Crucially, they were able to show that these precursors were not solid, but loose, transient structures which could be dissolved by changing the amount of sodium chloride in the presence of heparin, a naturally occurring anticoagulant in the human body. Solutions which had these cluster structures dissolved or suppressed showed nearly no formation of fibrils. The team proposed a mechanism by which the interaction between heparin and tau protein in the solution was reduced, making it harder to form clusters; the higher concentration of charged ions led to charged molecules like tau and heparin being more effectively hidden from each other through a process known as electrostatic "screening."
The team's findings suggest an entirely new paradigm for developing treatments, where one might target the reversible formation of precursors instead of trying to disassemble the final fibers. This is a crucial step forward for not only understanding and treating AD, but a wider range of neurodegenerative diseases, including Parkinson's disease.
This work was supported by JST SPRING Program Grant Number JPMJSP2156, JSPS KAKENHI Grant Numbers 22K07362, 25K21773, 24H00624, 22H05036, 23K21357, 25K02405, 23H00394, 23KK0133, and 20H01874, JST Moonshot R&D Program Grant Number JPMJMS2024, and AMED Grant Number 24wm0625303 and 25dk0207073.
