Elucidating molecular mechanisms governing tumor necrosis factor-alpha–mediated regulation of amyloid beta 42 uptake in blood-brain barrier endothelial cells

Abstract

Cerebrovascular inflammation is prevalent in a majority of patients with Alzheimer disease. Elevated levels of inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), circulating in the plasma have been shown to cause the inflammation of blood-brain barrier (BBB) endothelium lining the cerebral microvasculature in Alzheimer disease. The BBB inflammation triggered by exposure of TNF-α in the peripheral circulation can aggravate the accumulation of Aβ peptides in Alzheimer disease brain. In the current study, we have shown that infusion of wild-type mice with TNF-α led to an increase in permeability and influx of Aβ42 into the mice brain using dynamic single-photon emission computed tomography/computed tomography imaging. To corroborate these findings, we demonstrated that TNF-α increases Aβ42 accumulation in vitro in human cerebral microvascular endothelial cells /D3 and primary porcine brain endothelial cells. In addition, our results in human cerebral microvascular endothelial cells/D3 polarized monolayers show that TNF-α alters the expression of cofilin, actin, and dynamin, which are critical components for Aβ endocytosis by BBB endothelial cells. These results suggest a mechanistic pathway by which TNF-α may promote Aβ accumulation at the BBB and the underlying interactions between inflammation and Aβ exposure that drives BBB dysfunction. Hence, a therapeutic intervention aimed at addressing elevated TNF-α levels in Alzheimer disease may potentially reduce Aβ-related cerebrovascular dysfunction in Alzheimer disease brain. SIGNIFICANCE STATEMENT: Elevated plasma tumor necrosis factor-α drives Aβ pathology in Alzheimer disease, promoting cerebrovascular inflammation, but its role in endothelial Aβ uptake in the brain is unclear. This study shows tumor necrosis factor-α increases Aβ42 accumulation in the blood-brain barrier endothelium by altering the expression of blood-brain barrier endocytic proteins cofilin, actin, and dynamin.