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Structure determination of full-length amyloid fibrils of protein tau seeded by fibrils extracted from brains of Alzheimer’s Disease (AD) patients


EMSL Project ID
51231

Abstract

The accumulation of amyloid fibrils in the brain is associated with physiological events that trigger cascades of numerous neurodegenerative diseases. Here, we aim to use cryo-EM to determine the structures of both full-length fibrils of tau protein seeded by fibrils purified from autopsied Alzheimer’s disease (AD) brains and by unseeded fibrils. In both samples, tau fibrils are generated using a new method in which RNA is used as a natural co-factor for aggregation. We will compare the structure of tau fibrils seeded by AD fibrils extracted from autopsied brain patients with the non-seeded fibrils. The structures of the full-length tau fibrils will shed light on the mechanism of tau misfolding and will open new avenues for developing therapeutic inhibitors for Alzheimer’s disease. Using structure-based design, the new structures will enable us to design a new generation of small antibodies inhibitors (Nanobodies) that have the potential to block tau aggregation.

Project Details

Start Date
2019-12-20
End Date
2021-03-17
Status
Closed

Team

Principal Investigator

David Eisenberg
Institution
University of California, Los Angeles

Team Members

Romany Abskharon
Institution
University of California, Los Angeles

Qin Cao
Institution
University of California, Los Angeles

David Boyer
Institution
University of California, Los Angeles

Theo Humphreys
Institution
Oregon Health & Science University