Category: Preclinical Development
Purpose: Individuals with Type II diabetes mellitus (T2DM) demonstrate greater Alzheimer’s risk. Alzheimer’s patients exhibit several pathophysiological attributes of T2DM, such as cerebrovascular dysfunction as well as impaired brain energy metabolism. Previous studies have shown that amyloid beta (Aβ) peptides exacerbate hepatic and peripheral insulin resistance in Alzheimer’s mouse models carrying the amyloid precursor protein (APP) and human presenilin1 (PS1) transgenes (APP/PS1). These findings suggest that impairment of Aβ protein clearance, blood-brain barrier (BBB) dysfunction, and insulin resistance are associated with Alzheimer’s progression, although the underlying mechanisms remain unknown. We hypothesize that Aβ peptides cause cerebrovascular dysfunction, reduce insulin delivery to the brain, impair brain glucose transport, and trigger brain insulin resistance.
Methods: To test this hypothesis, the plasma pharmacokinetics and brain uptake kinetics of 18flurodeoxyglucose (18FDG) were investigated in wild-type (WT) and AD transgenic mice (APP/PS1), which overexpress Aβ peptides. WT mice were pre-infused via the internal carotid artery with or without Aβ40 or Aβ42, prior to femoral injection of 18FDG. The brain accumulation of 18FDG was monitored by dynamic PET/CT imaging. Patlak plots were constructed to determine the brain influx clearance of 18FDG. Western blot/immunohistochemistry was further conducted to investigate glucose transporter (GLUT1) expression on brain microcapillaries harvested from WT mice with/without Aβ protein infusion. Next, we investigated the impact of PI3K and AKT inhibitors on 18FDG transcytosis across human cerebral microvascular endothelial cell (hCMEC/D3) monolayers and assessed the effect of high-density lipoprotein (HDL) mimetic peptide, D-4F, in restoring the brain glucose metabolism in APP/PS1 transgenic mice.
Results: Patlak plots showed that the brain influx clearance of 18FDG was significantly reduced in WT mice following pre-infusion of Aβ40 or Aβ42. The 18FDG brain influx in the four groups of mice investigated in this study followed the rank order of: WT saline infusion > WT Aβ40 infusion ≈ WT Aβ42 infusion > APP/PS1 mice. Moreover, the expression of GLUT1 in brain microvessels decreased in WT mice following Aβ pre-infusion. In vitro studies conducted in hCMEC/D3 monolayers showed that the HDL mimetic, D-4F, partially mitigated alterations in AKT phosphorylation induced by Aβ. AKT has previously been shown to regulate GLUT1 activity at the BBB.
Conclusion: In summary, Aβ exposure impaired the brain glucose uptake and disrupted the PI3K/AKT pathway, which regulates glucose transport at the BBB. Furthermore, the HDL mimetic peptide, D-4F, showed the potential to rectify AKT phosphorylation and reinstate glucose transport at the BBB in AD brain.
Geoffry Curran– Mayo Clinic, Minneapolis, Minnesota
Teresa Decklever– Minneapolis, Minnesota
Paul Min– Minneapolis, Minnesota
Ling Li– Minneapolis, Minnesota
Karunya Kandimalla– University of Minnesota, Minneapolis, Minnesota