Intracerebral GM-CSF contributes to transendothelial monocyte migration in APP/PS1 Alzheimer’s disease mice

Abstract

Although tight junctions between human brain microvascular endothelial cells in the blood-brain barrier prevent molecules or cells in the bloodstream from entering the brain, in Alzheimer's disease, peripheral blood monocytes can ''open'' these tight junctions and trigger subsequent transendothelial migration. However, the mechanism underlying this migration is unclear. Here, we found that the CSF2RB, but not CSF2RA, subunit of the granulocyte-macrophage colony-stimulating factor receptor was overexpressed on monocytes from Alzheimer's disease patients. CSF2RB contributes to granulocyte-macrophage colony-stimulating factor-induced transendothelial monocyte migration. Granulocyte-macrophage colony-stimulating factor triggers human brain microvascular endothelial cells monolayer tight junction disassembly by downregulating ZO-1 expression via transcription modulation and claudin-5 expression via the ubiquitination pathway. Interestingly, intracerebral granulocyte-macrophage colony-stimulating factor blockade abolished the increased monocyte infiltration in the brains of APP/PS1 Alzheimer's disease model mice. Our results suggest that in Alzheimer's disease patients, high granulocyte-macrophage colony-stimulating factor levels in the brain parenchyma and cerebrospinal fluid induced blood-brain barrier opening, facilitating the infiltration of CSF2RB-expressing peripheral monocytes across blood-brain barrier and into the brain. CSF2RB might be useful as an Alzheimer's disease biomarker. Thus, our findings will help to understand the mechanism of monocyte infiltration in Alzheimer's disease pathogenesis.

Alpha-7 Nicotinic Receptor Signaling Pathway Participates in the Neurogenesis Induced by ChAT-Positive Neurons in the Subventricular Zone

“…The supernatant contained nuclear protein. Both membranous and nuclear fractions of the SVZ tissue were resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis to separate the proteins, which were then transferred to polyvinylidene fluoride membranes (Millipore, Billerica, MA, USA)[41]. Membranes were blocked with 5% bovine serum albumin (wt/vol) in Tris-buffered saline-0.1% Tween 20 (TBST) for 1 h at room temperature and incubated with one of the following primary antibodies: anti-FGFR1 (1:1000, Abcam, Cambridge, MA, USA), anti-phosphoinositide 3-kinase (PI3K; 1:1000, Abcam), anti-phospho-Akt (pAkt; 1:1000, Abcam), anti-Mash 1 (1:1000, Abcam), anti-DCX (1 µg/mL, Abcam), rabbit anti-glyceraldehyde 3-phosphate dehydrogenase (GAPDH; 1:2000, Sangon Biotech, Shanghai, China), or anti-Histone H3 (1:1000, Cell Signaling Technology, Danvers, MA, USA ) [42, 43].…”

ZO-1 expression is suppressed by GM-CSF via miR-96/ERG in brain microvascular endothelial cells

“…9 After 48 h, brains were separated for vibratome sectioning, and corpus striatums were lysed for Western blot. Immunohistofluorescence staining of corpus striatums (Figure 1 …”

“…The blood-brain barrier (BBB) separates the central nervous system (CNS) from the circulating blood, and forms a specific ''milieu'' for neurons by controlling the transport of substances including chemicals, 1,2 nutrients, 3,4 cells in the peripheral circulation, [5][6][7][8][9] polypeptides, and others. 10,11 The function of BBB mainly depends on brain microvascular endothelial cells (BMECs), which are characterized by complex tight junctions, reduced transcytosis, and some characteristic cell membrane transporters.…”

“…16,17 Granulocyte-macrophage colony-stimulating factor (GM-CSF) is produced in diverse CNS cells under pathological conditions, [18][19][20] and it can cross the BBB. 21 In view of the widespread expression of the GM-CSF receptor in migration of human monocytes across the BBB into the brain parenchyma, 9,19 which partially results from increasing of BBB permeability caused by reducing levels of zonula occludens-1 (ZO-1) and claudin-5 in brain microvascular endothelial cells (BMECs). 9 ZO-1 is a cytoplasmic accessory protein with multiple domains that is involved in tight junction formation.…”

“…21 In view of the widespread expression of the GM-CSF receptor in migration of human monocytes across the BBB into the brain parenchyma, 9,19 which partially results from increasing of BBB permeability caused by reducing levels of zonula occludens-1 (ZO-1) and claudin-5 in brain microvascular endothelial cells (BMECs). 9 ZO-1 is a cytoplasmic accessory protein with multiple domains that is involved in tight junction formation. 26 ZO-1 and other family members link the transmembrane proteins including claudins, occludins, and junction adhesion molecules (JAMs) to other cytoplasmic proteins and actin microfilaments.…”