Abstract
BackgroundBone marrow-derived microglia that originates in part from hematopoietic cells, and more particularly from monocytes preferentially attach to amyloid deposition in brains of Alzheimer’s disease (AD). However, the mechanism of monocytes recruited into the amyloid plaques with an accelerated process in AD is unclear.Methodology/Principal FindingsHere we reported that monocytes from AD patients express significantly higher chemokine (C-X-C motif) ligand 1 (CXCL1) compared to age-matched controls. AD patient’s monocytes or CXCL1-overexpressing THP-1 cells had enhanced ability of β-amyloid (Aβ)-induced transendothelial migration and Aβ-induced transendothelial migration for AD patient’s monocytes or CXCL1-overexpressing THP-1 cells was almost abrogated by anti-CXCL1 antibody. Furthermore, monocytes derived from a transgenic mouse model of AD also expressed significantly higher CXCL1. CD11b+CD45hi population of cells that were recruited from the peripheral blood were markedly bolcked in APP mouse brain by anti-CXCL1 antibody. Accordingly, in response to Aβ, human brain microvascular endothelial cells (HBMEC) significantly up-regulated CXC chemokine receptor 2 (CXCR2) expression, which was the only identified receptor for CXCL1. In addition, a high level expression of CXCR2 in HBMEC significantly promoted the CXCL1-overexpressing THP-1 cells transendothelial migration, which could be was abrogated by anti-CXCR2 antibody. Further examination of possible mechanisms found that CXCL1-overexpressing THP-1 cells induced transendothelial electrical resistance decrease, horseradish peroxidase flux increase, ZO-1 discontinuous and occludin re-distribution from insoluble to soluble fraction through interacting with CXCR2. ROCK inhibitor, Y27632, could block CXCL1-overexpressing THP-1 cells transendothelial migration, whereas other inhibitors had no effects.Conclusions/SignificanceThe present data indicate that monocytes derived from AD patients overexpressing CXCL1, which is a determinant for Aβ-induced transendothelial migration. CXCL1 expressed by monocytes and CXCR2 on HBMEC is involved in monocytes migrating from blood to brain in AD patients.
Highlights
Alzheimer’s disease (AD) is the most common form of agerelated dementia [1]
Our results show that monocytes derived from AD patients over-express Chemokine (C-X-C motif) ligand 1 (CXCL1) that interact with CXC chemokine receptor 2 (CXCR2) in human brain microvascular endothelial cells (HBMEC) to facilitate Aβ-induced transendothelial migration through the endothelial tight junction
The results showed that the expression of CXCL1 in AD patient’s monocytes was significantly higher than that in age-matched elderly controls (p < 0.01) (Figure 1)
Summary
Alzheimer’s disease (AD) is the most common form of agerelated dementia [1]. The pathological hallmarks of AD are senile plaques composed of beta-amyloid (Aβ), intracellular neurofibrillary tangles, accumulation of activated microglia and astrocytes around Aβ plaques, and degenerative neurons [2,3].Mounting evidence has demonstrated that microglia as the immune cells of the central nervous system (CNS) [4,5], which are responsible for patrolling the brain micro-environment and responding quickly in the presence of pathogens and brain damages, accumulate and surround the senile plaques in brains of post-morten AD patients and rodent transgenic models of AD [4,5,6,7,8,9]. Bone marrow-derived microglia that originates in part from hematopoietic cells, and more from monocytes preferentially attach to amyloid deposition in brains of Alzheimer’s disease (AD). Monocytes derived from a transgenic mouse model of AD expressed significantly higher CXCL1. In response to Aβ, human brain microvascular endothelial cells (HBMEC) significantly up-regulated CXC chemokine receptor 2 (CXCR2) expression, which was the only identified receptor for CXCL1. A high level expression of CXCR2 in HBMEC significantly promoted the CXCL1-overexpressing THP-1 cells transendothelial migration, which could be was abrogated by anti-CXCR2 antibody. Conclusions/Significance: The present data indicate that monocytes derived from AD patients overexpressing CXCL1, which is a determinant for Aβ-induced transendothelial migration. CXCL1 expressed by monocytes and CXCR2 on HBMEC is involved in monocytes migrating from blood to brain in AD patients
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