Abstract
BackgroundAlzheimer’s disease is widely described since the discovery of histopathological lesions in Mrs. Auguste Deter in 1906. However to date, there is no effective treatment to deal with the many cellular and molecular alterations. The complexity is even higher with the growing evidence of involvement of the peripheral blood mononuclear cells (PBMCs). Indeed, monocytes and T cells are shown in the cerebral parenchyma of AD patients, and these cells grafted to the periphery are able to go through the blood-brain barrier (BBB) in transgenic mouse models. It is known that BBB is disrupted at a late stage of AD. Chemokines represent major regulators of the transmigration of PBMCs, but many data were obtained on AD animal models. No data are available on the role of AD BBB in a healthy brain parenchyma. Therefore, the purpose of this study was to analyze the longitudinal chemokine profile expression in a BBB model from AD transgenic mice versus wild-type (WT) mice.MethodsA primary mouse BBB model was used with a luminal compartment either AD or WT and an abluminal compartment WT consisting of astrocytes and microglia. PBMCs were extracted by a ficoll gradient and incubated in the transwell with a direct contact with the luminal side, including the endothelial cells and pericytes. Then, the complete BBB model was incubated during 48 h, before supernatants and cell lysates were collected. Chemokines were quantified by X-MAP® luminex technology.ResultsAbluminal CX3CL1 production increased in 12-month-old AD BBB while CX3CL1 levels decreased in luminal lysates. CCL3 in luminal compartment increased with aging and was significantly different compared to AD BBB at 12 months. In addition, abluminal CCL2 in 12-month-old AD BBB greatly decreased compared to levels in WT BBB. On the contrary, no modification was observed for CCL4, CCL5, and CXCL10.ConclusionThese first findings highlighted the impact of AD luminal compartment on chemokine signature in a healthy brain parenchyma, suggesting new therapeutic or diagnostic approaches.
Highlights
Alzheimer’s disease is widely described since the discovery of histopathological lesions in Mrs Auguste Deter in 1906
In order to check the tightness of the blood-brain barrier (BBB) after 48 h of peripheral blood mononuclear cells (PBMCs) incubation, we measured Trans-endothelial electrical resistance (TEER) only because the measurement of paracellular permeability with Dextran-FITC could interfere with the chemokine assay using the X-MAP® luminex technology with magnetic beads grafted with antibodies directed against antigens
Are grouped averages of TEER calculated and expressed in Ω cm2. We found that these values were comparable to those obtained before the addition of PBMCs regardless of the age and phenotype of the mice used to extract the cells that make up the BBB model
Summary
Alzheimer’s disease is widely described since the discovery of histopathological lesions in Mrs Auguste Deter in 1906. Protected by the blood-brain barrier (BBB), the Vérité et al Journal of Neuroinflammation (2018) 15:182 accumulate in AD brain [21,22,23] The role of these peripheral cells in parenchyma is debated, either favoring the increased microglia activation, Aβ deposition, impaired cognitive functions, secreting pro-inflammatory cytokines or playing a defense role to senescent microglia [24, 25]. For this last role, it was shown that monocytes would be more effective than resident microglia which expresses a negative genetic variant of Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) associated to a decreased plaque-associated microgliosis [26, 27]. At the later stages of the pathology, chemokines (CCL2, CCL3, CCL4, CXCL1) were mostly expressed in GFAP-positive astrocytes and were detected in few Iba-1-positive microglia and NeuN-positive neurons [42]
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