Figure 6.

Schematic diagram of NFT life cycle and the role of oligomers in NFT formation and disease progression. 1) Under normal conditions, tau participates in the association and dissociation of microtubules, conferring dynamics to the system. 2) Post-translational modifications of tau, e.g., phosphorylation, can dissociate tau from microtubules. This dissociation produces an increase in the cytosolic concentration of the protein that exceeds the minimal tau concentration necessary to support conformational changes and leads to an electrostatic modification in the molecule that enables it to form a side chain-side chain interaction, culminating in the formation of a tau-tau dimer. Once these dimers are formed and adopt a stable structure, they can begin a process of nucleation, forming oligomers. 3) Subsequently, tau continues the aggregation process and undergoes additional post-translational modifications, such as phosphorylation and ubiquitination. These oligomers (in 2 and 3) are highly toxic and can induce memory deficits in mice and seed the aggregation of monomeric unmodified tau. Then tau oligomers form tau filaments, termed PHFs; these tau structures undergo new modifications and form NFTs. 4) Finally, after cell death, NFTs maintain their flame shape and form “ghost tangles” or eNFTs. Dashed arrows indicate that extracellular tau oligomers can induce the aggregation of monomeric tau from healthy neurons.