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BioMed Research International
Volume 2015 (2015), Article ID 917156, 10 pages
Research Article

Inhibition of ACE Retards Tau Hyperphosphorylation and Signs of Neuronal Degeneration in Aged Rats Subjected to Chronic Mild Stress

1Molecular Pharmacology Unit, Department of Chemistry and Applied Biosciences, ETH Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
2International Neuroscience Institute (INI) Hannover, Rudolf-Pichlmayr-Strasse 4, 30625 Hannover, Germany
3Medical Research Centre (MRC), Ain Shams University Hospitals, Abassia, Cairo 11591, Egypt
4Institute of Pharmacology and Toxicology, Department of Medicine, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland

Received 20 August 2015; Accepted 12 November 2015

Academic Editor: Grazia D’Onofrio

Copyright © 2015 Said AbdAlla et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


With increasing life expectancy, Alzheimer’s disease (AD) and other types of age-associated dementia are on the rise worldwide. Treatment approaches for dementia are insufficient and novel therapies are not readily available. In this context repurposing of established drugs appears attractive. A well-established class of cardiovascular drugs, which targets the angiotensin II system, is such a candidate, which currently undergoes a paradigm shift with regard to the potential benefit for treatment of neurodegenerative symptoms. In search for additional evidence, we subjected aged rats to chronic unpredictable mild stress, which is known to enhance the development of AD-related neuropathological features. We report here that four weeks of chronic mild stress induced a strong upregulation of the hippocampal angiotensin-converting enzyme (Ace) at gene expression and protein level. Concomitantly, tau protein hyperphosphorylation developed. Signs of neurodegeneration were detected by the significant downregulation of neuronal structure proteins such as microtubule-associated protein 2 (Map2) and synuclein-gamma (Sncg). Ace was involved in neurodegenerative symptoms because treatment with the brain-penetrating ACE inhibitor, captopril, retarded tau hyperphosphorylation and signs of neurodegeneration. Moreover, ACE inhibitor treatment could counteract glutamate neurotoxicity by preventing the downregulation of glutamate decarboxylase 2 (Gad2). Taken together, ACE inhibition targets neurodegeneration triggered by environmental stress.