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Interactions between A? and mutated Tau lead to polymorphism and induce aggregation of A?-mutated tau oligomeric complexes.

ABSTRACT: 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.

SUBMITTER: Raz Y

PROVIDER: S-EPMC3741189 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Interactions between Aβ and mutated Tau lead to polymorphism and induce aggregation of Aβ-mutated tau oligomeric complexes.

Raz Yoav Y Miller Yifat Y

PloS one 20130812 8

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 dis ...[more]

PMID: 23951348

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Project description:Active Caspase-6 (Casp6) and Tau cleaved by Casp6 at amino acids 402 (Tau∆D402) and 421 (Tau∆D421) are present in early Alzheimer disease intraneuronal neurofibrillary tangles, which are made primarily of filamentous Tau aggregates. To assess whether Casp6 cleavage of Tau contributes to Tau pathology and Casp6-mediated age-dependent cognitive impairment, we generated transgenic knock-in mouse models that conditionally express full-length human Tau (hTau) 0N4R only (CTO) or together with human Casp6 (hCasp6) (CTC). Region-specific hippocampal and cortical hCasp6 and hTau expression were confirmed with western blot and immunohistochemistry in 2-25-month-old brains. Casp6 activity was confirmed with Tau∆D421 and Tubulin cleaved by Casp6 immunopositivity in 3-25-month-old CTC, but not in CTO, brains. Immunoprecipitated Tau∆D402 was detected in both CTC and CTO brains, but was more abundant in CTC brains. Intraneuronal hippocampal Tau hyperphosphorylation at S202/T205, S422, and T231, and Tau conformational change were absent in both CTC and CTO brains. A slight accumulation of Tau phosphorylated at S396/404 and S202 was observed in Cornu Ammonis 1 (CA1) hippocampal neuron soma of CTC compared to CTO brains. Eighteen-month-old CTC brains showed rare argentophilic deposits that increased by 25 months, whereas CTO brains only displayed them sparsely at 25 months. Tau microtubule binding was equivalent in CTC and CTO hippocampi. Episodic and spatial memory measured with novel object recognition and Barnes maze, respectively, remained normal in 3-25-month-old CTC and CTO mice, in contrast to previously observed impairments in ACL mice expressing equivalent levels of hCasp6 only. Consistently, the CTC and CTO hippocampal CA1 region displayed equivalent dendritic spine density and no glial inflammation. Together, these results reveal that active hCasp6 co-expression with hTau generates Tau cleavage and rare age-dependent argentophilic deposits but fails to induce cognitive deficits, neuroinflammation, and Tau pathology.

Dataset Information

Interactions between A? and mutated Tau lead to polymorphism and induce aggregation of A?-mutated tau oligomeric complexes.

Publications

Interactions between Aβ and mutated Tau lead to polymorphism and induce aggregation of Aβ-mutated tau oligomeric complexes.

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