Angiotensin-(1-7) administration attenuates Alzheimer's disease-like neuropathology in rats with streptozotocin-induced diabetes via Mas receptor activation.
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-β oligomer and both soluble and insoluble β-amyloid peptide 1-42 (Aβ 1-42) and Aβ 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.
Department of Geriatrics, the First Affiliated Hospital of Chongqing Medical University, Friendship Road 1, Yuan Jiagang, 400016 Chongqing, China.
Jin-Liang
JL
Chen
Department of Geriatrics, the First Affiliated Hospital of Chongqing Medical University, Friendship Road 1, Yuan Jiagang, 400016 Chongqing, China.
Dong-Ling
DL
Zhang
Department of Geriatrics, the First Affiliated Hospital of Chongqing Medical University, Friendship Road 1, Yuan Jiagang, 400016 Chongqing, China.
Yue
Y
Sun
Department of Geriatrics, the First Affiliated Hospital of Chongqing Medical University, Friendship Road 1, Yuan Jiagang, 400016 Chongqing, China.
Yu-Xing
YX
Zhao
Department of Geriatrics, the First Affiliated Hospital of Chongqing Medical University, Friendship Road 1, Yuan Jiagang, 400016 Chongqing, China.
Ke-Xiang
KX
Zhao
Department of Geriatrics, the First Affiliated Hospital of Chongqing Medical University, Friendship Road 1, Yuan Jiagang, 400016 Chongqing, China.
Die
D
Pu
Department of Geriatrics, the First Affiliated Hospital of Chongqing Medical University, Friendship Road 1, Yuan Jiagang, 400016 Chongqing, China. Electronic address: xiaoqian1956@126.com.
Qian
Q
Xiao
D000544:Alzheimer Disease / Q000473:pathology* / Q000517:prevention & control* / Q000523:psychology; D000803:Angiotensin I / Q000008:administration & dosage*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000473:pathology* / Q000517:prevention & control* / Q000523:psychology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D010446:Peptide Fragments / Q000008:administration & dosage*; D010766:Phosphorylation; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D013311:Streptozocin; D013569:Synapses / Q000187:drug effects / Q000648:ultrastructure; D016875:tau Proteins / Q000378:metabolism
C489131:Mapt protein, rat; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D016875:tau Proteins; D013311:Streptozocin; D000803:Angiotensin I; C118790:angiotensin I (1-7)
Alzheimer’s disease; amyloid-β; angiotensin-(1–7); diabetes mellitus; tau