Interactions between Aβ and mutated Tau lead to polymorphism and induce aggregation of Aβ-mutated tau oligomeric complexes.
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.
Department of Chemistry, Ben‑Gurion University of the Negev, Beer-Sheva, Israel.
Yoav
Y
Raz
Yifat
Y
Miller
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D057180:Frontotemporal Dementia / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D016874:Neurofibrillary Tangles; D011110:Polymorphism, Genetic; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016875:tau Proteins