PXD057653

PXD057653 is an original dataset announced via ProteomeXchange.

Title	Cross interactions of Aβ peptides implicated in Alzheimer’s disease shape amyloid oligomer structures and aggregation
Description	A defining hallmark of Alzheimer's disease (AD) is the synaptic aggregation of the amyloid beta (Aβ) peptide. In vivo, Aβ production results in a diverse mixture of variants, of which Aβ40, Aβ42, and Aβ43 are profusely present in the AD brain, and their relative abundance is recognised to play a role in disease onset and progression. Nonetheless, the occurrence of Aβ40, Aβ42, and Aβ43 hetero-oligomerisation and the subsequent effects on Aβ aggregation remain elusive and were investigated here. Using thioflavin-T (ThT) monitored aggregation assays and native mass spectrometry coupled to ion mobility analysis (IM-MS), we first show that all Aβ peptides are aggregation-competent and self-assemble into homo-oligomers with distinct conformational populations, which are more pronounced between Aβ40 than the longer variants. ThT assays were then conducted on binary mixtures of Aβ variants, revealing that Aβ42 and Aβ43 aggregate independently from Aβ40, but significantly speed-up Aβ40 fibrillation. Aβ42 and Aβ43 were observed to aggregate concurrently and mutually accelerate fibril formation, which likely involves hetero-oligomerisation. Accordingly, native MS analysis revealed pairwise oligomerisation between all variants, with the formation of heterodimers and heterotrimers. Interestingly, IM-MS indicates that hetero-oligomers containing longer Aβ variants are enriched in conformers with lower collision-cross sections when compared to their homo-oligomer counterparts. This suggests that Aβ42 and Aβ43 are capable of remodelling oligomer structure towards a higher compaction level. Altogether, our findings provide a mechanistic description for the hetero-oligomerisation of Aβ variants implicated in AD, contributing to rationalising their in vivo proteotoxic interplay.
HostingRepository	PRIDE
AnnounceDate	2025-01-31
AnnouncementXML	Submission_2025-01-31_03:58:24.318.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Tanja Habeck
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Synapt MS

Revision	Datetime	Status	ChangeLog Entry
0	2024-11-08 01:02:55	ID requested
⏵ 1	2025-01-31 03:58:24	announced

10.1021/ACSCHEMNEURO.4C00492;

submitter keyword: Amyloid beta, protein aggregation, native ion mobility mass spectrometry

Frederik Lermyte
contact affiliation	Technical University of Darmstadt, Clemens-Schöpf Institute of Organic Chemistry and Biochemistry, 64287 Darmstadt, Germany
contact email	frederik.lermyte@tu-darmstadt.de
lab head
Tanja Habeck
contact affiliation	Department of Chemistry, Institute of Chemistry and Biochemistry, Technical University of Darmstadt, 64287 Darmstadt
contact email	tanja.habeck@tu-darmstadt.de
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/01/PXD057653

PRIDE project URI

• PRIDE
  1. PXD057653
     1. Label: PRIDE project
     2. Name: Cross interactions of Aβ peptides implicated in Alzheimer’s disease shape amyloid oligomer structures and aggregation