Amyloid Beta Peptides Inhibit Glucose Transport at the Blood-brain Barrier by Disrupting Insulin-Akt Pathway in Alzheimer's Disease
Disruptions in glucose uptake and metabolism in the brain are implicated in metabolic disorders and Alzheimers disease (AD). Toxic soluble amyloid-beta (sA{beta}) peptides accumulating in the brain and plasma of AD patients were suggested to promote blood-brain barrier (BBB) dysfunction, brain hypometabolism, and cognitive decline. Exposure to sA{beta} peptides is reported to interfere with glucose metabolism in the brain parenchyma, although their effects on the BBB have not been fully characterized. Our data showed that the brain uptake of glucose surrogate, [18F]-fluorodeoxyglucose (18FDG), was reduced significantly in APP/PS1 transgenic mice (overproduce A{beta}) compared to wild-type (WT) mice. In addition, the influx rate of 18FDG was also decreased in both A{beta}40 and A{beta}42 pre-infused mice compared to control mice. Glucose is primarily delivered from blood into the brain via glucose transporter 1 (GLUT1). The confocal microscopy experiment showed that A{beta}40 and A{beta}42 peptides significantly decreased GLUT1 expression in polarized human cerebral microvascular endothelial cell (hCMEC/D3) monolayers. Insulin-AKT pathway has been observed to induce glucose uptake via regulating the expression of TXNIP, the only -arrestin protein known to bind to thioredoxin. We found that A{beta}40 and A{beta}42 peptides decreased p-AKT and increased TXNIP expression in the hCMEC/D3 cell monolayers. MK2206, a kinase inhibitor of AKT, was used to confirm that inhibition of insulin/AKT pathway reduced GLUT1 expression in an insulin-independent manner in the hCMEC/D3 cell monolayers. These results suggest that inhibitory effects of sA{beta} on GLUT1 expression are mediated by inhibition of the insulin/AKT pathway. The role of TXNIP on endothelial GLUT1 expression was investigated using resveratrol, which has been reported to downregulate TXNIP overexpression. Consistently, resveratrol treatment led to a significant increase in GLUT1 expression in the hCMEC/D3 cell monolayers. Furthermore, by co-incubation of resveratrol and sA{beta} peptides in hCMEC/D3 cell monolayers, we found that resveratrol rectified the aberrant TXNIP expression caused by sA{beta} peptides. Together, these findings provide novel evidence that toxic sA{beta} peptide exposure inhibits glucose transport at the BBB by decreasing GLUT1 expression via the insulin/Akt/TXNIP axis.