The blood–brain barrier (BBB) plays an important role in the maintenance of the brain homeostasis, and its proper functions are warranted by the interplay between different cellular components (endothelial cells, astrocytes and pericytes). BBB dysfunctions in pathological conditions, and particularly in Alzheimer's disease, have been documented. Here, using an in vitroBBB model, the interaction between endothelial cells and astrocytes exposed to Aβ1-42 was investigated. Human endothelial cells, cultured in monolayer or co-cultured with astrocytes, were exposed to Aβ1-42 (2 μM for 18 h). Aβ induced dysfunction of endothelial barrier, as assessed by enhanced permeability to FITC-conjugated dextran and reduced expression of claudin-5; these modifications were observed in the co-culture model, but not in endothelial cells cultured in monolayer. Similarly, Aβ-induced damage at the barrier was observed when endothelial cells were challenged in the presence of conditioned medium generated by astrocytes previously exposed to Aβ (ACM Aβ). Endothelial barrier damages were associated with enhanced matrix metalloprotease 9 (MMP9) activity, known to mediate claudin-5 disruption. These events were not related to the direct effects played by Aβ on endothelial cells, but they were rather the consequence of Aβ-induced vascular endothelial growth factor (VEGF) expression in astrocytes. Indeed, when vascular endothelial growth factor expression was down-regulated in astrocytes, neither barrier properties or MMP9 expression in endothelial cells were affected after Aβ exposure both in the co-culture model or in the presence of ACM Aβ. These data point out the importance of astrocytes’ mediation in inducing endothelial sensitivity to Aβ1-42.

Astrocytes contribute to Aβ-induced blood brain barrier damage through activation of endothelial MMP9

Merlo S;SORTINO, Maria Angela
2017-01-01

Abstract

The blood–brain barrier (BBB) plays an important role in the maintenance of the brain homeostasis, and its proper functions are warranted by the interplay between different cellular components (endothelial cells, astrocytes and pericytes). BBB dysfunctions in pathological conditions, and particularly in Alzheimer's disease, have been documented. Here, using an in vitroBBB model, the interaction between endothelial cells and astrocytes exposed to Aβ1-42 was investigated. Human endothelial cells, cultured in monolayer or co-cultured with astrocytes, were exposed to Aβ1-42 (2 μM for 18 h). Aβ induced dysfunction of endothelial barrier, as assessed by enhanced permeability to FITC-conjugated dextran and reduced expression of claudin-5; these modifications were observed in the co-culture model, but not in endothelial cells cultured in monolayer. Similarly, Aβ-induced damage at the barrier was observed when endothelial cells were challenged in the presence of conditioned medium generated by astrocytes previously exposed to Aβ (ACM Aβ). Endothelial barrier damages were associated with enhanced matrix metalloprotease 9 (MMP9) activity, known to mediate claudin-5 disruption. These events were not related to the direct effects played by Aβ on endothelial cells, but they were rather the consequence of Aβ-induced vascular endothelial growth factor (VEGF) expression in astrocytes. Indeed, when vascular endothelial growth factor expression was down-regulated in astrocytes, neither barrier properties or MMP9 expression in endothelial cells were affected after Aβ exposure both in the co-culture model or in the presence of ACM Aβ. These data point out the importance of astrocytes’ mediation in inducing endothelial sensitivity to Aβ1-42.
2017
Alzheimer's disease; claudin-5; neurovascular unit; tight junctions; VEGF
File in questo prodotto:
File Dimensione Formato  
jnc.14068_Astrocytes_contribute.pdf

accesso aperto

Tipologia: Versione Editoriale (PDF)
Dimensione 1.68 MB
Formato Adobe PDF
1.68 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11769/30896
Citazioni
  • ???jsp.display-item.citation.pmc??? 39
  • Scopus 63
  • ???jsp.display-item.citation.isi??? 63
social impact