Amyloidogenesis of Tau protein

Abstract

The role of microtubule-associated protein Tau in neurodegeneration has been extensively investigated since the discovery of Tau amyloid aggregates in the brains of patients with Alzheimer's disease (AD). The process of formation of amyloid fibrils is known as amyloidogenesis and attracts much attention as a potential target in the prevention and treatment of neurodegenerative conditions linked to protein aggregation. Cerebral deposition of amyloid aggregates of Tau is observed not only in AD but also in numerous other tauopathies and prion diseases. Amyloidogenesis of intrinsically unstructured monomers of Tau can be triggered by mutations in the Tau gene, post-translational modifications, or interactions with polyanionic molecules and aggregation-prone proteins/peptides. The self-assembly of amyloid fibrils of Tau shares a number of characteristic features with amyloidogenesis of other proteins involved in neurodegenerative diseases. For example, in vitro experiments have demonstrated that the nucleation phase, which is the rate-limiting stage of Tau amyloidogenesis, is shortened in the presence of fragmented preformed Tau fibrils acting as aggregation templates ("seeds"). Accordingly, Tau aggregates released by tauopathy-affected neurons can spread the neurodegenerative process in the brain through a prion-like mechanism, originally described for the pathogenic form of prion protein. Moreover, Tau has been shown to form amyloid strains-structurally diverse self-propagating aggregates of potentially various pathological effects, resembling in this respect prion strains. Here, we review the current literature on Tau aggregation and discuss mechanisms of propagation of Tau amyloid in the light of the prion-like paradigm.

Keywords: Alzheimer's disease; Tau protein; amyloidogenesis; protein aggregation; tauopathies.

Figure 1

The domain organization of Tau. (A) There are 6 major Tau isoforms in the human brain: 2N4R, 1N4R, 0N4R, 2N3R, 1N3R, 0N3R. Molecules of these isoforms consist of two main domains: the projection domain that protrudes from the microtubule surface and the microtubule‐binding domain (MBD) which has high affinity for MTs. The isoforms differ in the number of N‐terminal inserts (N) and repeats (R) within microtubule‐binding repeats (MTBRs) region. The MTBRs are located within the MBD. The 4 repeats (4R) isoforms contain two hexapeptide motifs (PHF6* and PHF6) and two cysteines (C291 and C322), whereas 3R isoforms have only one hexapeptide motif (PHF6) and cysteine (C322). The longest isoform (2N4R, 441 amino acid residues) contains two inserts (2N) at the N terminus which are followed by the proline‐rich region (P1, P2) and MTBRs (composed of 4R). The third proline‐rich region (P3) follows the R4. Regions rich in negative (‐) and positive (+) charges are indicated. Tau peptides and polypeptides used as models to study amyloidogenesis include PHF6* and PHF6 (A) as well as K18 (4R), K19 (3R) and PHF43 (B). The predicted structure of Tau polypeptide (267‐312, corresponding to a fragment of the repeat region) in a MT‐bound conformation revealed by NMR spectroscopy is shown in (C) (PDB: 2MZ7,292). Note local enrichment in secondary structures. The structure was visualized in PyMOL293

Figure 2

The scheme of nucleated formation of Tau amyloid aggregates. (A) Intrinsically unstructured monomers of Tau (indicated in blue) do not acquire one specific conformation, but rather undergo transitions from one accessible conformational state to another. It is assumed that the formation of structured amyloid assemblies from unstructured monomers of Tau requires partial folding. It has been proposed that an amyloid‐competent conformer of Tau (indicated in green) is initially formed. It is also hypothesized that such competent monomers assemble into nuclei of Tau amyloidogenesis. Formation of the nuclei is a rate‐limiting stage and is followed by the rapid growth of fibrils. The tips of the amyloid fibril can act as templates incorporating the competent conformers leading to the elongation of the fibril. Hence, the number of available amyloid ends determines the rate of amyloidogenesis. Fragmentation of amyloid aggregates (usually accomplished in vitro by sonication of mature fibrils) produces short fragments called seeds, which can recruit native and amyloidogenic monomers leading to rapid growth of amyloid assemblies. (B) The scheme of kinetics of unseeded and seeded fibrillization of Tau

Figure 3

Amyloid fibrils of Tau visualized by TEM. Recombinant human Tau forms polymorphic fibrils in vitro. These assemblies may resemble amyloid fibrils found in tauopathies. (A) SFs formed by recombinant human full‐length Tau (2N4R, 441 amino acids). (B) PHFs formed by the K18 peptide. The scale bar is 100 nm

Figure 4

Hypothetical pathways in seeded fibrillization of Tau leading to strains. Tau is able to form structurally distinct amyloid seeds, depending on aggregation conditions. In the upper (A) and middle (B) panels, two types of Tau seeds are presented as single filaments (assembled in condition A indicated in blue) or paired filaments (assembled in condition B indicated in grey). According to the conformational memory hypothesis, these seeds recruit Tau monomers (in green) and convert them into strains which are molecular copies of the maternal seeds even if aggregation environment favors formation of alternative amyloid assemblies. Alternatively, strains may “switch” via conformational transition in which one amyloid seed may induce formation of a strain which may have a different structure. In the bottom (C) panel, two types of seeds are presented in condition D (in brown) that favors assembly of seed D. Conformational drift hypothesis postulates that upon change of aggregation environment, a minor conformer (in this case seed C) may gain a selective advantage, replicating its conformation and dominating the population over time