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Poly(ADP-ribose) polymerase-1 regulates microglia mediated decrease of endothelial tight junction integrity

Abbas Rezaeian Mehrabadi¹, Minna A Korolainen², Gary Odero¹

¹Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB, Canada; Neuroscience Research Program, Kleysen Institute for Advanced Medicine, Health Sciences Center, Winnipeg, MB, Canada.

Neurochemistry International

|May 3, 2017

Abstract:

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 (Aβ) -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 Aβ-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 Aβ. Aβ induced microglial release of nitric oxide (NO) and tumour necrosis factor alpha (TNFα), which resulted in reduced endothelial expression of TJPs and increased paracellular permeability. Microglial PARP-1 inhibition attenuated these Aβ-induced events. These findings demonstrate that PARP-1 mediated microglial responses (NO and TNFα) 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.

Insights

Alzheimer's disease pathology involves microglia that damage the blood-brain barrier (BBB). Inhibiting poly(ADP-ribose) polymerase-1 (PARP-1) in microglia prevents amyloid-beta-induced BBB disruption, offering a potential therapeutic strategy.

Area of Science:

Neuroscience
Immunology
Cell Biology

Background:

Alzheimer's disease (AD) is characterized by neuronal damage, reactive gliosis, and compromised blood-brain barrier (BBB) integrity.
Microglia, the brain's immune cells, are closely linked to the BBB, and their pro-inflammatory responses during AD may exacerbate BBB damage.

Purpose of the Study:

To investigate the direct impact of amyloid-beta (Aβ)-stimulated microglia on BBB integrity using co-culture models.
To determine if modulating microglial phenotype via poly(ADP-ribose) polymerase-1 (PARP-1) inhibition can reverse microglial-induced BBB damage.

Main Methods:

Co-culture of primary murine microglia with mouse brain endothelial cells (bEnd3) and murine astrocytes.
Assessment of tight junction protein (TJP) expression (ZO-1, occludin) in endothelial cells.
Measurement of glial fibrillary acidic protein (GFAP) in astrocytes.
Analysis of microglial nitric oxide (NO) and tumor necrosis factor alpha (TNFα) release.
Evaluation of PARP-1 inhibition effects on microglial responses and BBB integrity.

Main Results:

Unstimulated microglia enhanced TJP expression, while Aβ-stimulated microglia reduced ZO-1 and occludin levels in endothelial cells.
Aβ-stimulated microglia increased GFAP expression in co-cultured astrocytes, indicating astrogliosis.
Aβ induced microglial release of NO and TNFα, leading to decreased TJP expression, increased endothelial permeability, and astrogliosis.
PARP-1 inhibition in microglia attenuated Aβ-induced BBB damaging effects.

Conclusions:

PARP-1-mediated microglial responses, including NO and TNFα release, directly impair BBB integrity by degrading TJPs, increasing permeability, and inducing astrogliosis.
PARP-1 acts as a key modulator of microglial phenotype, and its inhibition can prevent microglial-driven BBB damage.
Targeting microglial PARP-1 presents a potential therapeutic strategy for mitigating BBB dysfunction in Alzheimer's disease.

Read full analysis

Keywords:

Amyloid beta Astrocyte Endothelia Microglia PARP-1 Tight junction

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