DOI: 10.1002/alz.082750 ISSN: 1552-5260

A brain‐seeded fibril amplification models the aggregation process of tau in Alzheimer’s disease for drug discovery

Alessia Santambrogio, Michael Metrick, Thomas Löhr, Robert Horne, Michele Vendruscolo
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Geriatrics and Gerontology
  • Neurology (clinical)
  • Developmental Neuroscience
  • Health Policy
  • Epidemiology



The microtubule‐associated protein tau is implicated in the development of a class of diverse neurodegenerative disorders, referred to as tauopathies, with symptoms of dementia and parkinsonism. Tauopathies comprise more than 20 clinicopathological entities, including Alzheimer’s disease, which accounts for 70% of dementia cases worldwide. In combination with clinical diagnosis and neuropathology, the reconstruction of different tau filaments by cryogenic electron microscopy (cryo‐EM) further points to the presence of distinct tau folds. The knowledge of these disease‐specific aggregate conformers provides a platform for the establishment of novel diagnostic methods and more tailored therapeutic approaches.


In order to investigate this problem, this project aims to selectively amplify tau in vitro from human brain homogenates affected by Alzheimer’s disease (AD) and Pick’s diseases (PiD). Kinetic analysis for drug discovery for the specific process of tau aggregation that takes place in Alzheimer’s disease was performed.


Strain discrimination was achieved, with a significant acceleration relative to the off‐target control, suggesting formation of two different fibril structures. Cryo‐EM was performed to confirm whether the in vitro AD‐like tau aggregates resembled those extracted from brains.We identify specific tau aggregation inhibitors, through in silico docking to binding sites on the surface of the cryo‐EM structure of tau fibrils adopting an AD fold.


The application of this line of research is illustrated by a study of the aggregation kinetics of AD‐like tau fibrils, and of its potential in drug discovery. In perspective, the approach that we present offer novel opportunities for the systematic in vitro study of the tau aggregation process as it may happen in the human brain.


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