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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 (<jats:italic>Ace<\/jats:italic>) 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 (<jats:italic>Map2<\/jats:italic>) and synuclein-gamma (<jats:italic>Sncg<\/jats:italic>).<jats:italic>Ace<\/jats:italic>was involved in neurodegenerative symptoms because treatment with the brain-penetrating<jats:italic>ACE<\/jats:italic>inhibitor, captopril, retarded tau hyperphosphorylation and signs of neurodegeneration. Moreover,<jats:italic>ACE<\/jats:italic>inhibitor treatment could counteract glutamate neurotoxicity by preventing the downregulation of glutamate decarboxylase 2 (<jats:italic>Gad2<\/jats:italic>). Taken together,<jats:italic>ACE<\/jats:italic>inhibition targets neurodegeneration triggered by environmental stress.<\/jats:p>","DOI":"10.1155\/2015\/917156","type":"journal-article","created":{"date-parts":[[2015,11,30]],"date-time":"2015-11-30T21:45:54Z","timestamp":1448919954000},"page":"1-10","source":"Crossref","is-referenced-by-count":29,"title":["Inhibition of ACE Retards Tau Hyperphosphorylation and Signs of Neuronal Degeneration in Aged Rats Subjected to Chronic Mild Stress"],"prefix":"10.1155","volume":"2015","author":[{"given":"Said","family":"AbdAlla","sequence":"first","affiliation":[{"name":"Molecular Pharmacology Unit, Department of Chemistry and Applied Biosciences, ETH Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahmed","family":"el Hakim","sequence":"additional","affiliation":[{"name":"International Neuroscience Institute (INI) Hannover, Rudolf-Pichlmayr-Strasse 4, 30625 Hannover, 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