Endothelial leakiness elicited by amyloid protein aggregation

Yuhuan Li, Nengyi Ni, Myeongsang Lee, Wei Wei, Nicholas Andrikopoulos, Aleksandr Kakinen, Thomas P. Davis, Yang Song (), Feng Ding (), David Tai Leong () and Pu Chun Ke ()
Additional contact information
Yuhuan Li: Fudan University
Nengyi Ni: National University of Singapore, Department of Chemical and Biomolecular Engineering
Myeongsang Lee: Clemson University
Wei Wei: Southwest University
Nicholas Andrikopoulos: Monash University
Aleksandr Kakinen: The University of Queensland
Thomas P. Davis: The University of Queensland
Yang Song: Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences
Feng Ding: Clemson University
David Tai Leong: National University of Singapore, Department of Chemical and Biomolecular Engineering
Pu Chun Ke: Monash University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Alzheimer’s disease (AD) is a major cause of dementia debilitating the global ageing population. Current understanding of the AD pathophysiology implicates the aggregation of amyloid beta (Aβ) as causative to neurodegeneration, with tauopathies, apolipoprotein E and neuroinflammation considered as other major culprits. Curiously, vascular endothelial barrier dysfunction is strongly associated with Aβ deposition and 80-90% AD subjects also experience cerebral amyloid angiopathy. Here we show amyloid protein-induced endothelial leakiness (APEL) in human microvascular endothelial monolayers as well as in mouse cerebral vasculature. Using signaling pathway assays and discrete molecular dynamics, we revealed that the angiopathy first arose from a disruption to vascular endothelial (VE)-cadherin junctions exposed to the nanoparticulates of Aβ oligomers and seeds, preceding the earlier implicated proinflammatory and pro-oxidative stressors to endothelial leakiness. These findings were analogous to nanomaterials-induced endothelial leakiness (NanoEL), a major phenomenon in nanomedicine depicting the paracellular transport of anionic inorganic nanoparticles in the vasculature. As APEL also occurred in vitro with the oligomers and seeds of alpha synuclein, this study proposes a paradigm for elucidating the vascular permeation, systemic spread, and cross-seeding of amyloid proteins that underlie the pathogeneses of AD and Parkinson’s disease.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-024-44814-1 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-44814-1

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-44814-1

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().