Elucidating Molecular Mechanisms Governing TNF-Alpha-Mediated Regulation of Amyloid Beta 42 Uptake in Blood-Brain Barrier Endothelial Cells

Abstract Cerebrovascular inflammation is prevalent in a majority of Alzheimer’s patients. Inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), circulating in the plasma have been shown to cause the inflammation of blood-brain barrier (BBB) endothelium lining the cerebral microvasculature. The BBB inflammation has been implicated in the increase of toxic Aβ accumulation within Alzheimer’s disease (AD) brain. TNF-alpha in the peripheral circulation can aggravate the accumulation of amyloid-beta (Aβ) peptides in Alzheimer’s disease brain. In the current study, we have shown that the exposure to TNF-alpha leads to an increase in Aβ42 accumulation in mice and BBB endothelial cells in vitro. Moreover, dynamic SPECT/CT imaging in wild-type (WT) mice infused with TNF-alpha increased the permeability and influx of Aβ42 into the mice brain. In addition, our results show that TNF-alpha modifies the expression of cofilin, actin, and dynamin, which are critical components for Aβ endocytosis by BBB endothelial cells. These results offer a mechanistic understanding of how TNF-alpha 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 cerebrovascular inflammation in Alzheimer’s disease may potentially reduce Aβ induced cerebrovascular toxicity in Alzheimer’s disease brain. Significance statement Increased levels of TNF-alpha circulating in the plasma are considered significant factors in the consequences of Aβ pathology in Alzheimer’s disease, where it can promote cerebrovascular inflammation and BBB dysfunction. However, the role of TNF-alpha, in exacerbating Aβ pathology by increasing Aβ accumulation at the BBB endothelial cells remains only partially understood. In this study, we demonstrated that TNF-alpha enhances Aβ42 accumulation in the BBB endothelium by altering the expression of the BBB endocytosis machinery, specifically cofilin, actin, and dynamin. These findings are anticipated to contribute to the development of therapeutic approaches aimed at addressing elevated cytokine levels in Alzheimer’s disease. Graphical Abstract