Disruptions in glucose and amyloid-beta transport in mouse models manifesting metabolic syndrome

Studies in humans and murine models have pointed towards a possible link between metabolic syndrome, which shows insulin resistance and metabolic dysregulation, and Alzheimer's disease (AD) pathology marked by amyloid-beta (A{beta}) accumulation and hypometabolism in the brain. Yet, the underlying biological mechanisms by which metabolic syndrome affects these pathological changes in AD brain remain unknown. We hypothesized that insulin resistance is responsible for alterations in blood-brain barrier (BBB) transport of A{beta} peptides and glucose. This hypothesis was tested by employing radiolabeled ligands (125I-A{beta}40, 125I-A{beta}42, and 18F-FDG) in high-fat diet (HFD)-fed mouse models that manifest metabolic syndrome. Further, we assessed alterations in the expression of various molecular mediators within the brain microcapillaries harvested from both low-fat diet (LFD)-fed and HFD-fed mice. Our findings show that HFD-fed mice developed peripheral insulin resistance and obesity. In addition, HFD-fed mice demonstrated an increase in the influx rate of A{beta} peptides and a reduction in 18F-FDG (a glucose surrogate) influx rate compared to LFD-fed mice. These transport changes are associated with the increase in the BBB endothelial expression of RAGE (receptor to traffic A{beta} from plasma-to-brain) and reduction of GLUT1 (glucose transporter) expression in HFD-fed mice compared to LFD-fed mice. Moreover, disruption in insulin signaling, as indicated by reduced pAKT and pERK expression, was observed in HFD-fed mice. Inhibiting AKT or ERK phosphorylation resulted in similar changes in A{beta} and glucose uptake in polarized BBB endothelial cell monolayers in vitro. These results indicate that high-fat diet induced metabolic syndrome may lead to BBB dysfunction, characterized by increased plasma-to-brain A{beta} trafficking and diminished glucose transport at the BBB, thereby aggravating the expression of AD pathological hallmarks.