Involvement of Rat Hippocampal Astrocytes in β-Amyloid-Induced Angiogenesis and Neuroinflammation

Abstract

Although Alzheimer's disease (AD) is considered a neurodengenerative disorders, in the last few years a large amount of evidence has suggested that it is also a vascular pathology characterized by increased capillary density and expression of angiogenic factors. In AD the endothelium degenerates, promoting local neuroinflammation and activation of brain endothelium, perivascular microglia, pericytes, astrocytes. Excess tumor necrosis factor (TNF) in the cerebrospinal fluid (CSF), at a concentration of 25 times higher than in the control group, has been demonstrated in AD. Recent studies provide evidence that treatment with TNF-α antagonists may result in a rapid cognitive improvement in AD patients. In the present work we investigated the role of astrocytes in AD angiogenesis and neuroinflammation by means of conditioned media of untreated and Aβ-treated rat hippocampal astrocytes (RHAs) on rat microvascular endothelial cells (RCECs). The results demonstrated that RHA media increase RCEC proliferation and capillary-like structure formation. Moreover RHAs secrete IL-1β and, only after the Aβ1-42 treatment, TNF-α promotes RCEC release of IL-1β, IL-6 and TNF-α. The removal of IL-1β, TNF-α and/or VEGF, a strong angiogenic inducer highly over-expressed in AD brains, by means of specific antibody-coated beads in RHA media affects RCEC release of IL-1β, IL-6 and TNF-α. We hypothesised that astrocytes contribute to AD angiogenesis and neuroinflammation by the direct release of pro-inflammatory cytokines. The effect of an anti-inflammatory agent, such as etanercept, decreased RCEC in vitro cytokine release. This could be compared to the effect found in our experiments with antibody anti TNF-α-coated beads.

Adjusting the compass: new insights into the role of angiogenesis in Alzheimer’s disease

“…These cytokines can then induce VEGF expression [56], yielding the growth of new blood vessels. Cultured astrocytes stimulated with Aβ [57,58] release neuroinflammatory cytokines, resulting in the increased expression of VEGF. In mice, the reduction of Aβ-induced neuroinflammation [59] and angiogenesis [60] using the drug thalidomide has been documented.…”

The role of inflammatory processes in Alzheimer’s disease

“…In addition, microvessels in AD patients also express the angiogenic substances angiopoietin-2 and vascular endothelial growth factor (VEGF) , and the integrin aVb3, a marker of angiogenesis, is also elevated in many brain regions in AD (Desai et al 2009), which might account for the increased levels of capillary density observed in AD patients (Fioravanzo et al 2010). Brain capillary endothelial cells have also been shown to proliferate in response to NGF, express NGF receptors, and secrete NGF after inflammation (Moser et al 2004).…”

Pathogenic Angiogenic Mechanisms in Alzheimer's Disease

“…This establishes a cycle of neurotoxicity and death, instituted by the discharge of thrombin following Aβ-induced neuroinflammatory responses [60]. Other studies further support the interaction of Aβ with thrombin and fibrin throughout the clotting cascade, to increase neurovascular damage and neuroinflammation [61][62][63]. Astrocytes, cultured in vitro and stimulated with Aβ, showed a release of neuroinflammatory cytokines that resulted in the increased expression of VEGF [49,50].…”