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

Abstract Aims To investigate restorative effects of the receptor for advanced glycation end products (RAGE)-specific inhibitor FPS-ZM1 on abnormal amyloid β (Aβ) influx across the blood brain-barrier (BBB) and cognitive deficits in db/db mice. Methods Aβ influx across the BBB was determined by intra-arterial infusion of 125 I-Aβ 1-40 . Receptor for advanced glycation end products (RAGE), Aβ, NF-κB 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 Aβ influx across the BBB and expression of RAGE participating in Aβ influx, consequently decreased hippocampal Aβ 1-40 and Aβ 1-42 in db/db mice. After FPS-ZM1 treatment, NF-κB 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 Aβ 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.