Soluble aggregates of the amyloid‐β protein selectively stimulate permeability in human brain microvascular endothelial monolayers

Abstract

Cerebral amyloid angiopathy associated with Alzheimer’s disease is characterized by cerebrovascular deposition of the amyloid-β protein (Aβ). Aβ elicits a number of morphological and biochemical alterations in the cerebral microvasculature, which culminate in hemorrhagic stroke. Among these changes, compromise of the blood-brain barrier has been described in Alzheimer’s disease brain, transgenic animal models of Alzheimer’s disease, and cell culture experiments. In the current study, presented data illustrates that isolated soluble Aβ1-40 aggregates, but not unaggregated monomer or mature fibril, enhance permeability in human brain microvascular endothelial monolayers. Aβ1-40-induced changes in permeability are paralleled by both a decrease in transendothelial electrical resistance and a re-localization of the tight junction associated protein zonula occludin-1 away from cell borders and into the cytoplasm. Small soluble Aβ1-40 aggregates are confirmed to be the most potent stimulators of endothelial monolayer permeability by establishing an inverse relationship between average aggregate size and stimulated changes in diffusional permeability coefficients. These results support previous findings demonstrating that small soluble Aβ1-40 aggregates are also primarily responsible for endothelial activation, suggesting that these same species may elicit other changes in the cerebrovasculature associated with cerebral amyloid angiopathy and Alzheimer’s disease.

Protection of the Blood-Brain Barrier by Pentosan Against Amyloid-β-Induced Toxicity

“…Aβ 1−40 at doses exceeding 5 µM increased the paracellular permeability in bovine brain endothelial cells [19]. It also induced a marked elevation in the permeability for the paracellular tracer 70 kDa FITC-dextran in an immortalized human brain endothelial cell line, hCMEC/D3 cells [58] and for the transcellular marker albumin in human brain microvascular endothelial monolayers between passages 4-8 [20].…”

“…Monolayer integrity of cerebral endothelial cells is also affected by Aβ peptides. Increased permeability for paracellular markers induced by Aβ 25−35 and Aβ 1−40 was detected in rat [18], bovine [19], and human brain microvascular endothelial cells [20].…”

A 1-42-RAGE Interaction Disrupts Tight Junctions of the Blood-Brain Barrier Via Ca2+-Calcineurin Signaling

“…The cells achieved confluence within 3 d of seeding. The permeability was measured using fluorescein isothiocyanateconjugated dextran (FD-40, MW 40,000; Sigma-Aldrich) (Gonzalez-Velasquez et al, 2008). FD-40 was added to the apical compartment at 0.1 g/ml.…”

Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease

“…The BBB endothelial cells respond to inflammatory stimuli such as cytokines, 186 LPS,187,188 Ab,[189][190][191] and a truncated tau fragment 192 by activating signaling pathways that result in the upregulation of proinflammatory second messengers and reactive oxygen/ nitrogen species, ultimately causing BBB disruption and paracrine activation of surrounding cells that are responsive to such stimuli, 66,198 and this corresponds with impaired Ab efflux. 66,198 In contrast to AD, decreased function of these transporters after LPS was not attributed to reduced protein levels or oxidative damage.…”

“…The BBB endothelial cells respond to inflammatory stimuli such as cytokines, 186 LPS, 187,188 Ab, [189][190][191] and a truncated tau fragment 192 by activating signaling pathways that result in the upregulation of proinflammatory second messengers and reactive oxygen/ nitrogen species, ultimately causing BBB disruption and paracrine activation of surrounding cells that are responsive to such stimuli, such as astrocytes 193 and pericytes 153,194 of the NVU. Inflammation impairs systemic clearance of Ab by the liver and kidneys, as well as bulk flow of CSF.…”