Tau filaments from multiple cases of sporadic and inherited Alzheimer\u2019s disease adopt a common fold

Benjamin Falcon,Michel Goedert,Alexey G Murzin,Bernardino Ghetti,Manuel Schweighauser,Holly J Garringer,Sjors H W Scheres,Wenjuan Zhang,Ruben Vidal

doi:10.1007/s00401-018-1914-z

Abstract

The ordered assembly of tau protein into abnormal filaments is a defining characteristic of Alzheimer’s disease (AD) and other neurodegenerative disorders. It is not known if the structures of tau filaments vary within, or between, the brains of individuals with AD. We used a combination of electron cryo-microscopy (cryo-EM) and immuno-gold negative-stain electron microscopy (immuno-EM) to determine the structures of paired helical filaments (PHFs) and straight filaments (SFs) from the frontal cortex of 17 cases of AD (15 sporadic and 2 inherited) and 2 cases of atypical AD (posterior cortical atrophy). The high-resolution structures of PHFs and SFs from the frontal cortex of 3 cases of AD, 2 sporadic and 1 inherited, were determined by cryo-EM. We also used immuno-EM to study the PHFs and SFs from a number of cortical and subcortical brain regions. PHFs outnumbered SFs in all AD cases. By cryo-EM, PHFs and SFs were made of two C-shaped protofilaments with a combined cross-β/β-helix structure, as described previously for one case of AD. The higher resolution structures obtained here showed two additional amino acids at each end of the protofilament. The immuno-EM findings, which indicated the presence of repeats 3 and 4, but not of the N-terminal regions of repeats 1 and 2, of tau in the filament cores of all AD cases, were consistent with the cryo-EM results. These findings show that there is no significant variation in tau filament structures between individuals with AD. This knowledge will be crucial for understanding the mechanisms that underlie tau filament formation and for developing novel diagnostics and therapies.

Highlights

Alzheimer’s disease (AD) is the most common neurodegenerative disorder [33]
paired helical filaments (PHFs) and straight filaments (SFs) were present in a ratio of approximately 4:1
Weaker densities extending from the N- and C-terminal regions of the core, described for filaments extracted from AD case 1 [14], were observed, as were the densities interacting with the sidechains of K317, T319, and K321

Summary

Introduction

The vast majority of cases are sporadic, with age being the main predisposing factor. Inheritance of the ε4 allele of the apolipoprotein E gene (APOE) is a major genetic risk factor for sporadic AD [37]. All cases of AD are characterised by abundant intraneuronal neurofibrillary lesions of filamentous tau [4, 22, 41, 42] and extracellular deposits of filamentous β-amyloid (Aβ) [16, 27] in the cerebral cortex and other brain regions. Atypical forms of AD differ from typical forms by clinical presentation and the brain areas most severely affected by neurofibrillary lesions and Aβ deposits [15].

Methods

Results

Conclusion