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Synergistic interactions between repeats in tau protein and A? amyloids may be responsible for accelerated aggregation via polymorphic states.

ABSTRACT: Amyloid plaques and neurofibrillary tangles simultaneously accumulate in Alzheimer's disease (AD). It is known that A? and tau exist together in the mitochondria; however, the interactions between A? oligomers and tau are controversial. Moreover, it is still unclear which specific domains in the tau protein can interact with A? oligomers and what could be the effect of these interactions. Herein, we examine three different A?-tau oligomeric complexes. These complexes present interactions of A? with three domains in the tau protein; all contain high ?-structure propensity in their R2, R3, and R4 repeats. Our results show that, among these, A? oligomers are likely to interact with the R2 domain to form a stable complex with better alignment in the turn region and the ?-structure domain. We therefore propose that the R2 domain can interact with soluble A? oligomers and consequently promote aggregation. EM and AFM images and dimensions revealed highly polymorphic tau aggregates. We suggest that the polymorphic tau and A?-tau aggregates may be largely due to repeat sequences which are prone to variable turn locations along the tau repeats.

SUBMITTER: Miller Y

PROVIDER: S-EPMC3109766 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Synergistic interactions between repeats in tau protein and Aβ amyloids may be responsible for accelerated aggregation via polymorphic states.

Miller Yifat Y Ma Buyong B Nussinov Ruth R

Biochemistry 20110518 23

Amyloid plaques and neurofibrillary tangles simultaneously accumulate in Alzheimer's disease (AD). It is known that Aβ and tau exist together in the mitochondria; however, the interactions between Aβ oligomers and tau are controversial. Moreover, it is still unclear which specific domains in the tau protein can interact with Aβ oligomers and what could be the effect of these interactions. Herein, we examine three different Aβ-tau oligomeric complexes. These complexes present interactions of Aβ w ...[more]

PMID: 21506544

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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.

Dataset Information

Synergistic interactions between repeats in tau protein and A? amyloids may be responsible for accelerated aggregation via polymorphic states.

Publications

Synergistic interactions between repeats in tau protein and Aβ amyloids may be responsible for accelerated aggregation via polymorphic states.

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