Abstract
Background: In Alzheimer’s disease (AD) neuronal degeneration is associated with gliosis and infiltration of peripheral blood mononuclear cells (PBMCs), which participate in neuroinflammation. Defects at the blood-brain barrier (BBB) facilitate PBMCs migration towards the central nervous system (CNS) and in particular CD4+ T cells have been found in areas severely affected in AD. However, the role of T cells, once they migrate into the CNS, is not well defined. CD4+ cells interact with astrocytes able to release several factors and cytokines that can modulate T cell polarization; similarly, astrocytic properties are modulated after interaction with T cells.Methods: In in vitro models, astrocytes were primed with β-amyloid (Aβ; 2.5 μM, 5 h) and then co-cultured with magnetically isolated CD4+ cells. Cytokines expression was evaluated both in co-cultured CD4+ cells and astrocytes. The effects of this crosstalk were further evaluated by co-culturing CD4+ cells with the neuronal-like SH-SY5Y cell line and astrocytes with endothelial cells.Results: The pattern of cytokines and trophic factors expressed by CD4+ cells were strongly modulated in the presence of Aβ-primed astrocytes. Specifically, the percentage of IL-4+ and IFNγ+ CD4+ cells was significantly increased and reduced, respectively. Further, increased BDNF mRNA levels were observed in CD4+ cells. When SH-SY5Y cells were co-cultured with astrocyte-conditioned CD4+ cells and exposed to Aβ, the reduction of the presynaptic protein synaptophysin was prevented with a BDNF-dependent mechanism. In astrocytes co-cultured with CD4+ cells, reduced mRNA levels of inflammatory cytokines and VEGF were observed. This was paralleled by the prevention of the reduction of claudin-5 when astrocytes were co-cultured with endothelial cells.Conclusion: Following Aβ exposure, there exists reciprocal crosstalk between infiltrating peripheral cells and astrocytes that in turn affects not only endothelial function and thus BBB properties, but also neuronal behavior. Since astrocytes are the first cells that lymphocytes interact with and are among the principal players in neuroinflammation occurring in AD, understanding this crosstalk may disclose new potential targets of intervention in the treatment of neurodegeneration.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder whose typical pathological hallmarks are β-amyloid (Aβ) plaques and neurofibrillary tangles
Starting from the interaction between T cells and astrocytes, the aim of our study was to analyze, in an in vitro system based on independent cellular cultures, the reciprocal interplay among infiltrating peripheral T cells, central nervous system (CNS) resident cells, including astrocytes and neurons, and endothelial cells and to establish whether this crosstalk can be modified when the different cell types are exposed to Aβ
peripheral blood mononuclear cells (PBMCs) migration rate through the barrier was significantly induced after 18 h of Aβ exposure (Figure 1A); this effect was accompanied by endothelial overexpression of the lower molecular weight (MW) intercellular adhesion molecule 1 (ICAM-1) glycoform (75 kDa), tightly involved in trans-endothelial migration (TEM) (Spampinato et al, 2019b), as shown by western blot analysis on endothelial extracts (Figure 1B)
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder whose typical pathological hallmarks are β-amyloid (Aβ) plaques and neurofibrillary tangles. The neuronal degeneration that characterizes the disease is associated with microgliosis and astrocytosis, causing an inflammatory state that has been described in the brain of AD patients. Peripheral inflammation can affect the central nervous system (CNS) and increased infiltration of immune cells in the brain of AD patients and corresponding animal models has been reported (Togo et al, 2002; Michaud et al, 2013; Zenaro et al, 2015). In Alzheimer’s disease (AD) neuronal degeneration is associated with gliosis and infiltration of peripheral blood mononuclear cells (PBMCs), which participate in neuroinflammation. Defects at the blood-brain barrier (BBB) facilitate PBMCs migration towards the central nervous system (CNS) and in particular CD4+ T cells have been found in areas severely affected in AD. CD4+ cells interact with astrocytes able to release several factors and cytokines that can modulate T cell polarization; astrocytic properties are modulated after interaction with T cells
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