The Dynamic Structure of Filamentous Tau

Abstract

Getting inside a fuzzy coat: The dynamic structure of the “fuzzy coat”, N‐ and C‐terminal sections around the core of the tau filament consists of over 200 amino acids, and has been characterized by NMR spectroscopy (see picture, model of the long range interactions). The results indicate how conformation specific antibodies bind to the tau protein (fibers of which are a characteristic symptom of Alzheimer disease).

Tau Oligomers Impair Artificial Membrane Integrity and Cellular Viability

“…Transmembrane spreading of Tau oligomers might well be involved in this initiation of widespread formation of fibrillar Tau pathology in AD. In support of this, formation of the MC1 epitope, as one of the earliest pathological alterations of Tau in AD (69), has been identified as occurring during oligomerization of Tau (70).…”

The fuzzy coat of pathological human Tau fibrils is a two-layered polyelectrolyte brush

“…The structural properties of the flexible terminal Tau domains from amyloid-like Tau fibrils are largely unknown (13,20). Immunogold-TEM images of full-length Tau fibrils, in which the N-and C-terminal Tau domains were labeled with gold-conjugated antibodies (21), suggested that the terminal Tau ends protrude from the fibrils and form a fuzzy coat around the rigid fibril core that consists of stacked TauRDs (Fig.…”

Distinct binding of PET ligands PBB3 and AV-1451 to tau fibril strains in neurodegenerative tauopathies

“…The discovery of tau gene mutations in familial tauopathy termed frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and investigations of various tau transgenic mouse lines provided compelling evidence for the mechanistic implication of tau abnormalities in neurotoxic insults (Lee et al, 2001). Composition of tau isoforms may give rise to conformational diversity of tau fibrils, which are ultrastructurally identified as paired helical filaments and straight filaments or ribbons (Bibow et al, 2011;Murray et al, 2014). These and other minor conformational variants, dubbed 'strains', determine subcellular, cellular and regional localizations of tau aggregates in close association with pathological and clinical phenotypes of each tauopathy (Feany and Dickson, 1995;Murray et al, 2014).…”

“…Characteristic morphologies known as paired helical filaments versus straight filaments (Bibow et al, 2011;Murray et al, 2014) reflect the different structures of these tau fibril assemblies which presumably reflects different conformational tau units in these filaments. Binding of 11 C-PBB3 to 4-repeat or 3-repeat lesions was much higher than that of 18 F-AV-1451, and this difference was greater than what could be seen in Alzheimer's disease and DNTC samples.…”