Antidiabetic drugs restore abnormal transport of amyloid-β across the blood-brain barrier and memory impairment in db/db mice

Previous studies have shown significant changes in amyloid-beta (A beta) transport across the blood-brain barrier (BBB) under diabetic conditions with hypoinsulinemia, which is involved in diabetes-associated cognitive impairment. Present study employed db/db mice with hyperinsulinemia to investigate changes in A beta transport across the BBB, hippocampal synaptic plasticity, and restorative effects of antidiabetic drugs. Our results showed that db/db mice exhibited similar changes in A beta transport across the BBB to that of insulin-deficient mice. Chronic treatment of db/db mice with antidiabetic drugs such as metformin, glibenclamide and insulin glargine significantly decreased A beta influx across the BBB determined by intra-arterial infusion of I-125-A beta(1-40), and expression of the receptor for advanced glycation end products (RAGE) participating in A beta influx. Insulin glargine, but not, metformin or glibenclamide increased A beta efflux across the BBB determined by stereotaxic intra-cerebral infusion of I-125-A beta(1-40), and expression of the low-density lipoprotein receptor related protein 1 (LRP1) participating in A beta efflux. Moreover, treatment with these drugs significantly decreased hippocampal A beta(1-40) or A beta(1-42) and inhibited neuronal apoptosis. The drugs also ameliorated memory impairment confirmed by improved performance on behavioral tasks. However, insulin glargine or glibenclamide, but not metformin, restored hippocampal synaptic plasticity characterized by enhancing in vivo long-term potentiation (LTP). Further study found that these three drugs significantly restrained NF-kappa B, but only insulin glargine enhanced peroxisome proliferator-activated receptor gamma (PPAR gamma) activity at the BBB in db/db mice. Our data indicate that the antidiabetic drugs can partially restore abnormal A beta transport across the BBB and memory impairment under diabetic context. (C) 2015 Elsevier Ltd. All rights reserved.