Synthesis and Characterization of Propeller- and Parallel-Type Full-Length Amyloid β40 Trimer Models.
Ayumi UchinoYumi IrieChihiro TsukanoTaiji KawaseKenji HiroseYusuke KageyamaIkuo TooyamaRyo C YanagitaKazuhiro IriePublished in: ACS chemical neuroscience (2022)
Oligomers of the amyloid β (Aβ) protein play a critical role in the pathogenesis of Alzheimer's disease. However, their heterogeneity and lability deter the identification of their tertiary structures and mechanisms of action. Aβ trimers and Aβ dimers may represent the smallest aggregation unit with cytotoxicity. Although propeller-type trimer models of E22P-Aβ40 tethered by an aromatic linker have recently been synthesized, they unexpectedly exhibited little cytotoxicity. To increase the flexibility of trimeric propeller-type models, we designed and synthesized trimer models with an alkyl linker, tert -butyltris-l-alanine ( t ButA), at position 36 or 38. In addition, we synthesized two parallel-type trimer models tethered at position 38 using alkyl linkers of different lengths, α,α-di-l-norvalyl-l-glycine (di-nV-Gly) and α,α-di-l-homonorleucyl-l-glycine (di-hnL-Gly), based on the previously reported toxic dimer model. The propeller-type E22P,V36 t ButA-Aβ40 trimer ( 4 ), which was designed to mimic the C-terminal anti-parallel β-sheet structures proposed by the structural analysis of 150 kDa oligomers of Aβ42, and the parallel-type E22P,G38di-nV-Gly-Aβ40 trimer ( 6 ) showed significant cytotoxicity against SH-SY5Y cells and aggregative ability to form protofibrillar species. In contrast, the E22P,G38 t ButA-Aβ40 trimer ( 5 ) and E22P,G38di-hnL-Gly-Aβ40 trimer ( 7 ) exhibited weak cytotoxicity, though they formed quasi-stable oligomers observed by ion mobility-mass spectrometry and native polyacrylamide gel electrophoresis. These results suggest that 4 and 6 could have some phase of the structure of toxic Aβ oligomers with a C-terminal hydrophobic core and that the conformation and/or aggregation process rather than the formation of stable oligomers contribute to the induction of cytotoxicity.
Keyphrases
- mass spectrometry
- biofilm formation
- high resolution
- ionic liquid
- magnetic resonance imaging
- induced apoptosis
- magnetic resonance
- escherichia coli
- oxidative stress
- cystic fibrosis
- cell death
- staphylococcus aureus
- amino acid
- candida albicans
- cell cycle arrest
- endoplasmic reticulum stress
- molecular dynamics simulations
- crystal structure
- contrast enhanced
- pi k akt
- solid state