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 Aβ peptide forms aggregates both with itself and with wild-type tau. By analogy, in FTDP-17, it is likely that there are interactions between Aβ and mutated tau, but the molecular mechanisms underlying such interactions remain to be elucidated. Thus, to investigate the interactions between Aβ and mutated tau, we constructed fourteen ∆K280 mutated tau-Aβ17-42 oligomeric complexes. In seven of the mutated tau-Aβ17-42 oligoemric complexes the mutated tau oligomers exhibited hydrophobic interactions in their core domain, and in the other seven mutated tau-Aβ17-42 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 Aβ oligomers: interactions of one monomer of the Aβ oligomer with one monomer of the mutated tau oligomer to form a single-layer conformation, and interactions of the entire Aβ oligomer with the entire mutated tau oligomer to form a double-layer conformation. We also considered parallel arrangements of Aβ trimers alternating with mutated tau trimers in a single-layer conformation. Our results demonstrate that in the interactions of Aβ and mutated tau oligomers, polymorphic mutated tau-Aβ17-42 oligomeric complexes were observed, with a slight preference for the double-layer conformation. Aβ trimers alternating with mutated tau trimers constituted a structurally stable confined β-structure, albeit one that was energetically less stable than all the other constructed models.
Highlights
Alzheimer’s disease (AD) is characterized by both senile plaques [1] and neurofibrillary tangles (NFTs) in the brain [2,3]
Since previous computational modeling studies have shown that hexamers are the minimal oligomeric size of amyloid to adopt a fibril-like structure [44,45], we sought to keep the number of structural models manageable with respect to computational power and timescale by constructing hexamers
The aggregation of Aβ into amyloid plaques is characteristic of AD, while the aggregation of mutated tau into NFTs is a process long known to be related to FTDP-17
Summary
Alzheimer’s disease (AD) is characterized by both senile plaques [1] and neurofibrillary tangles (NFTs) in the brain [2,3]. Despite extensive studies of tau aggregates, the detailed structures of tau oligomers and tau fibrils are still to be fully elucidated It is, known that the longest human tau isoform, hTau40 – observed in the central nervous system – consists of 441 residues. One of the best known mutations in FTDP-17 is the deletion ∆K280 mutation [27,28,29], which is located in the tau R2 repeat domain (residues 275-300) [30,31] This mutation has been shown to promote the aggregation of the tau protein by enabling it to better adopt a βstructure vis-à-vis wild-type tau [14,32]. We believe that it can pave the way to future therapeutic efforts for the synthesis of novel drugs for FTDP-17, AD and other tauopathies that aim to prevent interactions between mutated tau protein and Aβ
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
