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  • Title: Targeted inhibition of RAGE reduces amyloid-β influx across the blood-brain barrier and improves cognitive deficits in db/db mice.
    Author: Wang H, Chen F, Du YF, Long Y, Reed MN, Hu M, Suppiramaniam V, Hong H, Tang SS.
    Journal: Neuropharmacology; 2018 Mar 15; 131():143-153. PubMed ID: 29248482.
    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 125I-Aβ1-40. 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 Aβ1-40 and Aβ1-42 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.
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