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Mixed oligomers and monomeric amyloid-? disrupts endothelial cells integrity and reduces monomeric amyloid-? transport across hCMEC/D3 cell line as an in vitro blood-brain barrier model.

ABSTRACT: Senile amyloid plaques are one of the diagnostic hallmarks of Alzheimer's disease (AD). However, the severity of clinical symptoms of AD is weakly correlated with the plaque load. AD symptoms severity is reported to be more strongly correlated with the level of soluble amyloid-? (A?) assemblies. Formation of soluble A? assemblies is stimulated by monomeric A? accumulation in the brain, which has been related to its faulty cerebral clearance. Studies tend to focus on the neurotoxicity of specific A? species. There are relatively few studies investigating toxic effects of A? on the endothelial cells of the blood-brain barrier (BBB). We hypothesized that a soluble A? pool more closely resembling the in vivo situation composed of a mixture of A?40 monomer and A?42 oligomer would exert higher toxicity against hCMEC/D3 cells as an in vitro BBB model than either component alone. We observed that, in addition to a disruptive effect on the endothelial cells integrity due to enhancement of the paracellular permeability of the hCMEC/D3 monolayer, the A? mixture significantly decreased monomeric A? transport across the cell culture model. Consistent with its effect on A? transport, A? mixture treatment for 24h resulted in LRP1 down-regulation and RAGE up-regulation in hCMEC/D3 cells. The individual A? species separately failed to alter A? clearance or the cell-based BBB model integrity. Our study offers, for the first time, evidence that a mixture of soluble A? species, at nanomolar concentrations, disrupts endothelial cells integrity and its own transport across an in vitro model of the BBB.

SUBMITTER: Qosa H

PROVIDER: S-EPMC4133170 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Mixed oligomers and monomeric amyloid-β disrupts endothelial cells integrity and reduces monomeric amyloid-β transport across hCMEC/D3 cell line as an in vitro blood-brain barrier model.

Qosa Hisham H LeVine Harry H Keller Jeffrey N JN Kaddoumi Amal A

Biochimica et biophysica acta 20140702 9

Senile amyloid plaques are one of the diagnostic hallmarks of Alzheimer's disease (AD). However, the severity of clinical symptoms of AD is weakly correlated with the plaque load. AD symptoms severity is reported to be more strongly correlated with the level of soluble amyloid-β (Aβ) assemblies. Formation of soluble Aβ assemblies is stimulated by monomeric Aβ accumulation in the brain, which has been related to its faulty cerebral clearance. Studies tend to focus on the neurotoxicity of specific ...[more]

PMID: 24997450

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Dataset Information

Mixed oligomers and monomeric amyloid-? disrupts endothelial cells integrity and reduces monomeric amyloid-? transport across hCMEC/D3 cell line as an in vitro blood-brain barrier model.

Publications

Mixed oligomers and monomeric amyloid-β disrupts endothelial cells integrity and reduces monomeric amyloid-β transport across hCMEC/D3 cell line as an in vitro blood-brain barrier model.

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