The elusive tau molecular structures: can we translate the recent breakthroughs into new targets for intervention?

Abstract

Insights into tau molecular structures have advanced significantly in recent years. This field has been the subject of recent breakthroughs, including the first cryo-electron microscopy structures of tau filaments from Alzheimer's and Pick's disease inclusions, as well as the structure of the repeat regions of tau bound to microtubules. Tau structure covers various species as the tau protein itself takes many forms. We will here address a range of studies that help to define the many facets of tau protein structures and how they translate into pathogenic forms. New results shed light on previous data that need now to be revisited in order to up-date our knowledge of tau molecular structure. Finally, we explore how these data can contribute the important medical aspects of this research - diagnosis and therapeutics.

Keywords: Alzheimer’s disease diagnosis; Alzheimer’s disease; tau structure; tau aggregation; Amyloid; Tauopathies.

Fig. 1

Scheme of tau showing domain organization. Depending of the isoform, tau has an N-terminal extension with 0, 1, or 2 inserts (tau0N, tau1N, tau2N, respectively), the presence of N1 and N2 inserts depending on exon 2 and exon 3, respectively. The microtubule-binding region (MTBR) has three (tau3R) or four (tau4R) repeats, the presence of R2 depending on exon 10. MTBR repeats R1 to R4 (31 or 32 residues for each repeat and inter-repeat region) have similar sequences. The PHF6* and PHF6 peptides are located in R2 and R3, respectively. The longest tau isoform corresponds to 441 amino-acid residues (or tau2N4R) and the shortest to tau352 amino-acid residues (or tau0N3R). Tau fragments K18, K19 and dGAE are mentioned in the text. The proline-rich region or PRR has many phosphorylation sites, combination of pS202/pT205 and pS208 forms the AT8 monoclonal antibody epitope. Antibody 18F12 recognizes a conformational epitope at the junction of N1 and N2 inserts. The 18–28 motif of tau is primate specific

Fig. 2

Negative stain EM image of in vitro PHFs produced from dGAE in additive-free conditions at pH 7.4 and 37 °C [4]

Fig. 3

a Domain structure of tau2N4R with the location of potential zinc chelators shown in sticks (Cys, His, Asp, Glu). b Scheme of zinc chelation by the main binding sites located in R2 and R3 domains. c Hypothetical scheme of reversible zinc-induced aggregation

Fig. 4

Tau PET image in a patient with AD ( Mini Mental State Examination= 20/30), demonstrating close association between tau pathology (top) and cerebral glucose metabolism (FDG-PET, bottom). Images were acquired at Saint-Luc University Hospital (UCLouvain, Belgium)

Fig. 5

Comparison of tracer uptake patterns of F18-PI-2620 targeting tau and Neuraceq targeting β-amyloid plaques