Activation of Brain Endothelium by Soluble Aggregates of the Amyloid-β Protein Involves Nuclear Factor-κB

Abstract

Cerebrovascular accumulation of amyloid-β protein (Aβ) aggregates in Alzheimer's disease (AD) is proposed to contribute to disease progression and brain inflammation as a result of Aβ-induced increases in endothelial monolayer permeability and stimulation of the endothelium for cellular adhesion and transmigration. These deficiencies facilitate the entry of serum proteins and monocyte-derived microglia into the brain. In the current study, a role for nuclear factor-κB (NF-κB) in the activation of cerebral microvascular endothelial cells by Aβ is explored.Quantitative immunocytochemistry is employed to demonstrate that Aβ(1-40) preparations containing isolated soluble aggregates elicit the most pronounced activation and nuclear translocation of NF-κB. This rapid and transient response is observed down to physiological Aβ concentrations and parallels phenotypic changes in endothelial monolayers that are selectively elicited by soluble Aβ(1-40) aggregates. While monomeric and fibrillar preparations of Aβ(1-40) also activated NF-κB, this response was less pronounced, limited to a small cell population, and not coupled with phenotypic changes. Soluble Aβ(1-40) aggregate stimulation of endothelial monolayers for adhesion and subsequent transmigration of monocytes as well as increases in permeability were abrogated by inhibition of NF-κB activation. Together, these results provide additional evidence indicating a role for soluble Aβ aggregates in the activation of the cerebral microvascular endothelium and implicate the involvement of NF-κB signaling pathways in Aβ stimulation of endothelial dysfunction associated with AD.

Genistein inhibits aggregation of exogenous amyloid-beta1–40 and alleviates astrogliosis in the hippocampus of rats

“…According to previous data, however, inflammation-inducing agents such as Aβ trigger NF-κB activation in astrocytes (Gonzalez-Velasquez et al, 2011) leading to inflammatory response, and this activation can be inhibited by genistein (Hsieh et al, 2011).…”

Vascular dysfunction in the pathogenesis of Alzheimer's disease — A review of endothelium-mediated mechanisms and ensuing vicious circles

“…Isolated soluble A aggregates activated adhesion and transmigration of monocytes, whereas un-aggregated monomers and mature fibrils did not [138]. A further study from the same group also demonstrated an implication of the nuclear factor-kB (NF-kB) in mediating A -induced endothelial permeability to monocytes [140]. A -induced BBB permeability to mononuclear cells has also been demonstrated in vivo.…”

“…A also increases adherence and transmigration of monocytes across the BBB [43, 137,138], mediated by the transcription factor NF-kB [140]. Transmigrated monocytes undergo differentiation into microglia [139], and become activated in inflammatory conditions.…”

Preeclampsia and health risks later in life: an immunological link

“…Aggregated proteins such as TTR and Aβ are cytotoxic and have been confirmed to cause ER stress, oxidative stress, inflammation, anti-angiogenic factor release, inflammation, and apoptosis [67,[87][88][89][90][91][92]. Aβ aggregates are capable of activating glial cells and astrocytes as well as inducing release of proinflammatory cytokines and chemokines such as TNF-α and IL-1β [90][91][92][93]. In addition, Aβ has been shown to activate NF-kB signaling cascade in neurons, astrocytes, glial cells, and brain endothelial cells [92].…”

“…Aβ aggregates are capable of activating glial cells and astrocytes as well as inducing release of proinflammatory cytokines and chemokines such as TNF-α and IL-1β [90][91][92][93]. In addition, Aβ has been shown to activate NF-kB signaling cascade in neurons, astrocytes, glial cells, and brain endothelial cells [92].…”