2. Academic Validation
  3. Endothelial leakiness elicited by amyloid protein aggregation

Endothelial leakiness elicited by amyloid protein aggregation

  • Nat Commun. 2024 Jan 19;15(1):613. doi: 10.1038/s41467-024-44814-1.
Yuhuan Li # 1 2,  Nengyi Ni # 3,  Myeongsang Lee 4,  Wei Wei 5,  Nicholas Andrikopoulos 2 6,  Aleksandr Kakinen 7,  Thomas P Davis 7,  Yang Song 8,  Feng Ding 9,  David Tai Leong 10,  Pu Chun Ke 11 12
Affiliations

Affiliations

  • 1 Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, 200032, China.
  • 2 Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia.
  • 3 National University of Singapore, Department of Chemical and Biomolecular Engineering, 4 Engineering Drive 4, Singapore, 117585, Singapore.
  • 4 Department of Physics and Astronomy, Clemson University, Clemson, SC, 29634, USA.
  • 5 College of Veterinary Medicine, Southwest University, Chongqing, 402460, China.
  • 6 The Nanomedicine Center, The Great Bay Area National Institute for Nanotechnology Innovation, 136 Kaiyuan Avenue, Guangzhou, 510700, China.
  • 7 Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, 4072, Australia.
  • 8 State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China. yangsong@rcees.ac.cn.
  • 9 Department of Physics and Astronomy, Clemson University, Clemson, SC, 29634, USA. fding@clemson.edu.
  • 10 National University of Singapore, Department of Chemical and Biomolecular Engineering, 4 Engineering Drive 4, Singapore, 117585, Singapore. cheltwd@nus.edu.sg.
  • 11 Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia. pu-chun.ke@monash.edu.
  • 12 The Nanomedicine Center, The Great Bay Area National Institute for Nanotechnology Innovation, 136 Kaiyuan Avenue, Guangzhou, 510700, China. pu-chun.ke@monash.edu.
  • # Contributed equally.
PMID: 38242873 DOI: 10.1038/s41467-024-44814-1
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.

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