Site-specific chirality-conferred structural compaction differentially mediates the cytotoxicity of Aβ42

Gongyu Li, Chae Kyung Jeon, Min Ma, Yifei Jia, Zhen Zheng, Daniel G. Delafield, Gaoyuan Lu, Elena V. Romanova, Jonathan V. Sweedler, Brandon T. Ruotolo, Lingjun Li

Research output: Contribution to journalArticlepeer-review


Growing evidence supports the confident association between distinct amyloid beta (Aβ) isoforms and Alzheimer's Disease (AD) pathogenesis. As such, critical investigations seeking to uncover the translational factors contributing to Aβ toxicity represent a venture of significant value. Herein, we comprehensively assess full-length Aβ42 stereochemistry, with a specific focus on models that consider naturally-occurring isomerization of Asp and Ser residues. We customize various forms of d-isomerized Aβ as natural mimics, ranging from fragments containing a single d residue to full length Aβ42 that includes multiple isomerized residues, systematically evaluating their cytotoxicity against a neuronal cell line. Combining multidimensional ion mobility-mass spectrometry experimental data with replica exchange molecular dynamics simulations, we confirm that co-d-epimerization at Asp and Ser residues within Aβ42 in both N-terminal and core regions effectively reduces its cytotoxicity. We provide evidence that this rescuing effect is associated with the differential and domain-specific compaction and remodeling of Aβ42 secondary structure.

Original languageEnglish (US)
Pages (from-to)5936-5944
Number of pages9
JournalChemical Science
Issue number22
StatePublished - May 8 2023

ASJC Scopus subject areas

  • Chemistry(all)


Dive into the research topics of 'Site-specific chirality-conferred structural compaction differentially mediates the cytotoxicity of Aβ42'. Together they form a unique fingerprint.

Cite this