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Tau forms oligomeric complexes on microtubules that are distinct from tau aggregates.

ABSTRACT: Tau is a microtubule-associated protein, which promotes neuronal microtubule assembly and stability. Accumulation of tau into insoluble aggregates known as neurofibrillary tangles (NFTs) is a pathological hallmark of several neurodegenerative diseases. The current hypothesis is that small, soluble oligomeric tau species preceding NFT formation cause toxicity. However, thus far, visualizing the spatial distribution of tau monomers and oligomers inside cells under physiological or pathological conditions has not been possible. Here, using single-molecule localization microscopy, we show that tau forms small oligomers on microtubules ex vivo. These oligomers are distinct from those found in cells exhibiting tau aggregation and could be precursors of aggregated tau in pathology. Furthermore, using an unsupervised shape classification algorithm that we developed, we show that different tau phosphorylation states are associated with distinct tau aggregate species. Our work elucidates tau's nanoscale composition under nonaggregated and aggregated conditions ex vivo.

SUBMITTER: Gyparaki MT

PROVIDER: S-EPMC8126857 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:One of the main hallmarks of the fronto-temporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) is the accumulation of neurofibrillary tangles in the brain as an outcome of the aggregation of mutated tau protein. This process occurs due to a number of genetic mutations in the MAPT gene. One of these mutations is the ?K280 mutation in the tau R2 repeat domain, which promotes the aggregation vis-à-vis that for the wild-type tau. Experimental studies have shown that in Alzheimer's disease A? peptide forms aggregates both with itself and with wild-type tau. By analogy, in FTDP-17, it is likely that there are interactions between A? and mutated tau, but the molecular mechanisms underlying such interactions remain to be elucidated. Thus, to investigate the interactions between A? and mutated tau, we constructed fourteen ?K280 mutated tau-A?17-42 oligomeric complexes. In seven of the mutated tau-A?17-42 oligoemric complexes the mutated tau oligomers exhibited hydrophobic interactions in their core domain, and in the other seven mutated tau-A?17-42 oligoemric complexes the mutated tau oligomers exhibited salt-bridge interactions in their core domain. We considered two types of interactions between mutated tau oligomers and A? oligomers: interactions of one monomer of the A? oligomer with one monomer of the mutated tau oligomer to form a single-layer conformation, and interactions of the entire A? oligomer with the entire mutated tau oligomer to form a double-layer conformation. We also considered parallel arrangements of A? trimers alternating with mutated tau trimers in a single-layer conformation. Our results demonstrate that in the interactions of A? and mutated tau oligomers, polymorphic mutated tau-A?17-42 oligomeric complexes were observed, with a slight preference for the double-layer conformation. A? trimers alternating with mutated tau trimers constituted a structurally stable confined ?-structure, albeit one that was energetically less stable than all the other constructed models.

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Tau forms oligomeric complexes on microtubules that are distinct from tau aggregates.

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