An azobenzene photoswitch sheds light on turn nucleation in amyloid-β self-assembly

Todd M. Doran, Elizabeth A. Anderson, Sarah E. Latchney, Lisa A. Opanashuk, Bradley L. Nilsson

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Amyloid-β (Aβ) self-assembly into cross-β 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. Aβ fibrils feature a sheet-turn-sheet motif in the constituent β-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 β-hairpin mimetic to study the role turn nucleation plays on Aβ self-assembly. [3-(3-Aminomethyl)phenylazo] phenylacetic acid (AMPP) was incorporated into the putative turn region of Aβ42 to elicit temporal control over Aβ42 turn nucleation; it was hypothesized that self-assembly would be favored in the cis-AMPP conformation if β-hairpin formation occurs during Aβ self-assembly and that the trans-AMPP conformer would display attenuated fibrillization propensity. It was unexpectedly observed that the trans-AMPP Aβ42 conformer forms fibrillar constructs that are similar in almost all characteristics, including cytotoxicity, to wild-type Aβ42. Conversely, the cis-AMPP Aβ42 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 Aβ turn conformation provides significant insight into Aβ self-assembly. Specifically, Aβ mutants that adopt stable β-turns form aggregate structures that are unable to enter folding pathways leading to cross-β fibrils and cytotoxic prefibrillar intermediates.

Original languageEnglish (US)
Pages (from-to)211-220
Number of pages10
JournalACS Chemical Neuroscience
Volume3
Issue number3
DOIs
StatePublished - Mar 21 2012

Keywords

  • Alzheimer's disease
  • Amyloid-β
  • amyloid fibrils
  • azobenzene photoswitch
  • turn nucleation
  • β-turn

Fingerprint Dive into the research topics of 'An azobenzene photoswitch sheds light on turn nucleation in amyloid-β self-assembly'. Together they form a unique fingerprint.

Cite this