Increased Pro-Inflammatory Response by Dendritic Cells from Patients with Alzheimer's Disease

Abstract

Abstract. Alzheimer's disease (AD) is characterized by abnormal accumulation of amyloid-β peptide (Aβ) into extracellular fibrillar deposits, paralleled by chronic neuroinflammatory processes. Although Aβ seems to be causative in AD brain damage, the role of the immune system and its mechanisms still remain to be clarified. We have recently shown that normal monocyte-derived dendritic cells (MDDCs), when differentiated in the presence of Aβ1−42, acquire an inflammatory phenotype and a reduced antigen presenting ability. Here we studied MDDCs derived from AD patients in comparison with MDDCs obtained from healthy control subjects (HC). MDDCs from AD patients, at variance with HC-derived cells, were characterized by an augmented cell recovery, a consistent increase in the expression of the pro-inflammatory ICAM-1 molecule, a decrease in the expression of the co-stimulatory CD40 molecule, and an impaired ability to induce T cell proliferation. Furthermore, MDDCs from AD produced higher amounts of IL-6 than HC-derived cells, confirming the more pronounced pro-inflammatory features of these cells in AD patients. Consistent results have been also obtained with monocytes, the MDDC precursors. In fact, while unstimulated monocytes do not appear to be different in AD and HC, after stimulation with lipopolysaccharide, AD monocytes overexpressed ICAM-1 with respect to controls, suggesting that common pathways of monocyte activation and MDDC differentiation are altered in AD. Overall, these findings show that AD-linked dysregulated immune mechanisms exist, which lead to dendritic cell-mediated over-activation of inflammation and impaired antigen presentation, thus supporting the view that immune cell activation could play an important role in AD pathogenesis.

Role of neuroinflammation in neurodegeneration: new insights

“…Myeloid cells from memory-impaired individuals also have a greater stimulus-induced proinflammatory response [91], which mirrors animal studies demonstrating the same effect in bone marrow-derived macrophages from APP/PS1 mice [98]. However, it has been found that DCs from AD patients have a reduced ability to stimulate T cell proliferation [94]. The innate immune system provides the first line of defense against infectious agents, thus an altered response here can have severe consequences for the individual and their ability to control, and respond to, infection.…”

“…Indeed the population of circulating myeloid dendritic cells (DCs) is decreased in the elderly [92] and these cells are further reduced in AD [93]. AD patients had increased levels of ICAM-1 + monocyte-derived DCs [94] and increased expression of MHC class II and CD16 on CD14 + monocytes [95]. Saresella and colleagues also found a significant increase in IL-6- and IL-23-producing CD14 + monocyte/macrophages in AD patients, while IL-10 + cells were reduced [75].…”

Two Blood Monocytic Biomarkers (CCL15 and p21) Combined with the Mini-Mental State Examination Discriminate Alzheimer’s Disease Patients from Healthy Subjects

“…Monocytes migrate across a compromised blood-brain barrier and express chemokine receptors to guide immune cells to inflammatory sites [9,10,34,35,36]. Monocytic cell adhesion molecules are altered in AD patients [33,37]. Further, the expression of chemokine receptors and cytokines was found to be increased in PBMCs of AD patients [38].…”

Interleukin-18, From Neuroinflammation to Alzheimers Disease

“…Within this scenario, where A or other AD-related stressor factors could induce the release of IL-18, likely via PRR triggering, it is conceivable that this cytokine would exacerbate the release by neighboring glial cells or peripheral immune cells, of diverse toxic inflammatory molecules, which may lead to a vicious cycle where inflammatory processes contribute to different aspects of AD neurodegeneration. In keeping with a potential contribute of peripheral immune cells in amplifying the AD inflammatory milieu, we recently demonstrated that myeloidderived DCs obtained from AD patients show an over activated inflammatory state and a reduced antigen presenting ability, as compared to cells of healthy control subjects [132]. Since in a previous in vitro study we have shown that A treatment is able to sustain inflammation by driving monocyte differentiation towards an IL-18 producing DC phenotype [133], it is probable that IL-18 would exacerbate a neuroinflammatory responses in a AD-specific and DCdependent fashion also in vivo conditions.…”