ANGIOTENSIN-(1-7) ADMINISTRATION ATTENUATES ALZHEIMER'S DISEASE-LIKE NEUROPATHOLOGY IN RATS WITH STREPTOZOTOCIN-INDUCED DIABETES VIA MAS RECEPTOR ACTIVATION

摘要

Diabetes mellitus (DM) is associated with cognitive deficits and an increased risk of Alzheimer's disease (AD). Recently, a newly identified heptapeptide of the renin-angiotensin system (RAS), angiotensin-(1-7) [Ang-(1-7)], was found to protect against brain damage. This study investigated the effects of Ang-(1-7) on diabetes-induced cognitive deficits. Sprague-Dawley rats were randomly divided into four groups. Diabetes was induced via single i.p. streptozotocin (STZ) injections. Ten weeks after diabetes induction, rats in each group received an intracerebral-ventricular (ICV) infusion of either vehicle, Ang-(1-7) alone, or Ang-(1-7) + A779 daily for two weeks. At the end of the study, Morris water maze (MWM) tests were performed to test cognitive functions before the rats were euthanized. Ang-(1-7) treatment significantly reduced escape latencies in diabetic rats in acquisition trials and markedly enhanced platform area crossing frequency and time spent in the target quadrant in probe trials (3.0 +/- 0.39 vs. 1.0 +/- 0.33, 39.39 +/- 1.11% vs. 25.62 +/- 3.07%, respectively, P < 0.01). Ang-(1-7) treatment ameliorated damage to the ultrastructure of hippocampal synapses, reduced the expression of hippocampal phospho-tau at Ser396 (P < 0.01), Ser404 (P < 0.01) and Ser202/Thr205 (P < 0.05), and decreased amyloid-beta oligomer and both soluble and insoluble beta-amyloid peptide 1-42 (A beta 1-42) and A beta 1-40 levels (P < 0.01). These protective effects were significantly reversed by the co-administration of A779. These findings show that Ang-(1-7) is a promising therapeutic target for diabetes-induced cognitive impairment. The neuroprotective effects of Ang-(1-7) were mainly through Mas receptor (MasR) activation. (C) 2017 IBRO. Published by Elsevier Ltd. All rights reserved.