Research Paper Volume 12, Issue 14 pp 14819—14829
ACE2 activator diminazene aceturate ameliorates Alzheimer's disease-like neuropathology and rescues cognitive impairment in SAMP8 mice
- 1 School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, People's Republic of China
- 2 Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, People's Republic of China
- 3 Department of Pathology, Nanjing Brain Hospital, Nanjing Medical University, Nanjing 210029, People's Republic of China
Received: February 19, 2020 Accepted: June 4, 2020 Published: July 23, 2020https://doi.org/10.18632/aging.103544
How to Cite
Copyright © 2020 Duan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Previously, we revealed that brain Ang-(1-7) deficiency was involved in the pathogenesis of sporadic Alzheimer’s disease (AD). We speculated that restoration of brain Ang-(1-7) levels might have a therapeutic effect against AD. However, the relatively short duration of biological effect limited the application of Ang-(1-7) in animal experiments. Since Ang-(1-7) is generated by its metabolic enzyme ACE2, we then tested the efficacy of an ACE2 activator diminazene aceturate (DIZE) on AD-like neuropathology and cognitive impairment in senescence-accelerated mouse prone substrain 8 (SAMP8) mice, an animal model of sporadic AD. Eight-month-old SAMP8 mice were injected intraperitoneally with vehicle or DIZE once a day for 30 consecutive days. DIZE markedly elevated brain Ang-(1-7) and MAS1 levels. Meanwhile, DIZE significantly reduced the levels of Aβ1-42, hyperphosphorylated tau and pro-inflammatory cytokines in the brain. The synaptic and neuronal losses in the brain were ameliorated by DIZE. Importantly, DIZE improved spatial cognitive functions in the Morris water maze test. In conclusion, this study demonstrates that DIZE ameliorates AD-like neuropathology and rescues cognitive impairment in SAMP8 mice. These beneficial effects of DIZE may be achieved by activating brain ACE2/Ang-(1-7)/MAS1 axis. These findings highlight brain ACE2/Ang-(1-7)/MAS1 axis as a potential target for the treatment of sporadic AD.