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Poly(ADP-ribose) polymerase-1 regulates microglia mediated decrease of endothelial tight junction integrity
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DOI：10.1016/j.neuint.2017.04.014.png)
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Alzheimer's disease pathology includes, beside neuronal damage, reactive gliosis and reduced blood brain barrier (BBB) integrity. Microglia are intimately associated with the BBB and upon AD pathology, pro-inflammatory responses of microglia could contribute to BBB damage. To study whether microglia can directly affect BBB integrity, the effects of amyloid beta (A beta-stimulated primary murine microglia on co-cultured mouse brain endothelial cells (bEnd3) and murine astrocyte cultures were assessed. We also assessed whether microglial phenotype modulation via poly(ADP-ribose) polymerase-1 (PARP-1) inhibition/ablation can reverse microglial impact on these BBB forming cells. Unstimulated microglia promoted expression of tight junction proteins (TJPs), zonula ocluden-1 (ZO-1) and occludin in co-cultured endothelia cells, whereas A beta-stimulated microglia reduced endothelial expression of ZO-1 and occludin. Astrocytes co-cultured with microglia showed elevated glial fibrillary acidic protein (GFAP) expression, which was further increased if microglia had been stimulated with AO. A beta induced microglial release of nitric oxide (NO) and tumour necrosis factor alpha (TNF alpha), which resulted in reduced endothelial expression of TJPs and increased paracellular permeability. Microglial PARP-1 inhibition attenuated these A beta-induced events. These findings demonstrate that PARP-1 mediated microglial responses (NO and TNF alpha) can directly reduce BBB integrity by promoting TJP degradation, increasing endothelial cell permeability and inducing astrogliosis. PARP-1 as a modulator of microglial phenotype can prevent microglial BBB damaging events, and thus is a potential therapeutic target. (C) 2017 Elsevier Ltd. All rights reserved.
Keyword:
Amyloid beta
Astrocyte
Endothelia
Microglia
PARP-1
Tight junction
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