Elucidating Molecular Mechanisms Governing TNF-Alpha-Mediated Regulation of Amyloid Beta 42 Uptake in Blood-Brain Barrier Endothelial Cells
Cerebrovascular inflammation is prevalent in a majority of Alzheimers 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 A{beta} accumulation within Alzheimers disease (AD) brain. TNF-alpha in the peripheral circulation can aggravate the accumulation of amyloid-beta (A{beta}) peptides in Alzheimers disease brain. In the current study, we have shown that the exposure to TNF-alpha leads to an increase in A{beta}42 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 A{beta}42 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 A{beta} endocytosis by BBB endothelial cells. These results offer a mechanistic understanding of how TNF-alpha may promote A{beta} accumulation at the BBB and the underlying interactions between inflammation and A{beta} exposure that drives BBB dysfunction. Hence, a therapeutic intervention aimed at addressing cerebrovascular inflammation in Alzheimers disease may potentially reduce A{beta} induced cerebrovascular toxicity in Alzheimers disease brain. Significance statementIncreased levels of TNF-alpha circulating in the plasma are considered significant factors in the consequences of A{beta} pathology in Alzheimers disease, where it can promote cerebrovascular inflammation and BBB dysfunction. However, the role of TNF-alpha, in exacerbating A{beta} pathology by increasing A{beta} accumulation at the BBB endothelial cells remains only partially understood. In this study, we demonstrated that TNF-alpha enhances A{beta}42 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 Alzheimers disease. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=162 SRC="FIGDIR/small/635286v2_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@6b27a4org.highwire.dtl.DTLVardef@f7b37dorg.highwire.dtl.DTLVardef@28efbcorg.highwire.dtl.DTLVardef@193408c_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG