title: Inhibition of ACE Retards Tau Hyperphosphorylation and Signs of Neuronal Degeneration in Aged Rats Subjected to Chronic Mild Stress.
abstract: 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.
authors.affiliation: Molecular Pharmacology Unit, Department of Chemistry and Applied Biosciences, ETH Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
authors.forename: Said
authors.initials: S
authors.lastname: AbdAlla
authors.affiliation: International Neuroscience Institute (INI) Hannover, Rudolf-Pichlmayr-Strasse 4, 30625 Hannover, Germany.
authors.forename: Ahmed
authors.initials: A
authors.lastname: El Hakim
authors.affiliation: Medical Research Centre (MRC), Ain Shams University Hospitals, Abassia, Cairo 11591, Egypt.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Abdelbaset
authors.affiliation: Medical Research Centre (MRC), Ain Shams University Hospitals, Abassia, Cairo 11591, Egypt.
authors.forename: Yasser
authors.initials: Y
authors.lastname: Elfaramawy
authors.affiliation: Molecular Pharmacology Unit, Department of Chemistry and Applied Biosciences, ETH Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland ; Institute of Pharmacology and Toxicology, Department of Medicine, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
authors.forename: Ursula
authors.initials: U
authors.lastname: Quitterer
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage*; D000818:Animals; D002216:Captopril / Q000008:administration & dosage*; D005786:Gene Expression Regulation / Q000187:drug effects; D005968:Glutamate Decarboxylase / Q000096:biosynthesis; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis* / Q000235:genetics; D010766:Phosphorylation; D051381:Rats; D051845:gamma-Synuclein / Q000096:biosynthesis; D016875:tau Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D051845:gamma-Synuclein; D016875:tau Proteins; D002216:Captopril; C488034:ACE protein, human; D007703:Peptidyl-Dipeptidase A; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2