科研之友
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摘要
Amyloid-beta (A beta) self-assembly into cross-beta amyloid fibrils is implicated in a causative role in Alzheimer's disease pathology. Uncertainties persist regarding the mechanisms of amyloid self-assembly and the role of metastable prefibrillar aggregates. A beta fibrils feature a sheet-turn-sheet motif in the constituent beta-strands; as such, turn nucleation has been proposed as a rate-limiting step in the self-assembly pathway. Herein, we report the use of an azobenzene beta-hairpin mimetic to study the role turn nucleation plays on A beta self-assembly. [3-(3-Aminomethyl)phenylazo]phenylacetic acid (AMPP) was incorporated into the putative turn region of A beta 42 to elicit temporal control over A beta 42 turn nucleation; it was hypothesized that self-assembly would be favored in the cis-AMPP conformation if beta-hairpin formation occurs during A beta self-assembly and that the trans-AMPP conformer would display attenuated fibrillization propensity. It was unexpectedly observed that the trans-AMPP A beta 42 conformer forms fibrillar constructs that are similar in almost all characteristics, including cytotoxicity, to wild-type A beta 42. Conversely, the cis-AMPP A beta 42 congeners formed nonfibrillar, amorphous aggregates that exhibited no cytotoxicity. Additionally, cis-trans photoisomerization resulted in rapid formation of native-like amyloid fibrils and trans-cis conversion in the fibril state reduced the population of native-like fibrils. Thus, temporal photocontrol over A beta turn conformation provides significant insight into A beta self-assembly. Specifically, A beta mutants that adopt stable beta-turns form aggregate structures that are unable to enter folding pathways leading to cross-beta fibrils and cytotoxic prefibrillar intermediates.
- 出版日期2012-3
