Targeted inhibition of RAGE reduces amyloid-β influx across the blood-brain barrier and improves cognitive deficits in db/db mice

Aims: To investigate restorative effects of the receptor for advanced glycation end products (RAGE) specific inhibitor FPS-ZM1 on abnormal amyloid beta (A beta) influx across the blood brain-barrier (BBB) and cognitive deficits in db/db mice. Methods: A beta influx across the BBB was determined by intra-arterial infusion of I-125-A beta(1-40). Receptor for advanced glycation end products (RAGE), A beta, NF-kappa B p65, caspase-3, Bax, Bcl-2, PSD-95 and synaptophysin were assayed by Western blot, immunohistochemistry or RT-PCR. Apoptosis was quantified by TUNEL assay. In vivo hippocampal long term potentiation (LTP) recording, Golgi Staining, Morris water maze (MWM) task and Y-maze test were performed. Results: FPS-ZM1 (1.0 mg/kg i.p.) inhibited A beta influx across the BBB and expression of RAGE participating in A beta influx, consequently decreased hippocampal A beta(1-40) and A beta(1-42) in db/db mice. After FPS-ZM1 treatment, NF-kappa B signaling was inhibited, and neuronal apoptosis was reduced, which revealed by less TUNEL + cells, reduced caspase-3 activity and higher ratio of Bcl-2/Bax. In addition, FPS-ZM1 improved hippocampal plasticity evidenced by enhanced in vivo LTP and the restoration of spine deficit and increased PSD-95 expression in hippocampal neuron. Further studies found that FPS-ZM1 treatment alleviated cognitive deficits shown by better performance in behavioral tests, without significant metabolic effects on blood glucose, insulin and cerebral AGEs. Conclusion: Downregulation of abnormal A beta influx across the BBB by FPS-ZM1 at higher dosage contributes to reduced neuronal apoptosis, improved hippocampal plasticity and cognitive impairment in db/db mice. (C) 2017 Elsevier Ltd. All rights reserved.