title: Protective effects of testosterone on presynaptic terminals against oligomeric β-amyloid peptide in primary culture of hippocampal neurons.
abstract: Increasing lines of evidence support that testosterone may have neuroprotective effects. While observational studies reported an association between higher bioavailable testosterone or brain testosterone levels and reduced risk of Alzheimer's disease (AD), there is limited understanding of the underlying neuroprotective mechanisms. Previous studies demonstrated that testosterone could alleviate neurotoxicity induced by β-amyloid (Aβ), but these findings mainly focused on neuronal apoptosis. Since synaptic dysfunction and degeneration are early events during the pathogenesis of AD, we aim to investigate the effects of testosterone on oligomeric Aβ-induced synaptic changes. Our data suggested that exposure of primary cultured hippocampal neurons to oligomeric Aβ could reduce the length of neurites and decrease the expression of presynaptic proteins including synaptophysin, synaptotagmin, and synapsin-1. Aβ also disrupted synaptic vesicle recycling and protein folding machinery. Testosterone preserved the integrity of neurites and the expression of presynaptic proteins. It also attenuated Aβ-induced impairment of synaptic exocytosis. By using letrozole as an aromatase antagonist, we further demonstrated that the effects of testosterone on exocytosis were unlikely to be mediated through the estrogen receptor pathway. Furthermore, we showed that testosterone could attenuate Aβ-induced reduction of HSP70, which suggests a novel mechanism that links testosterone and its protective function on Aβ-induced synaptic damage. Taken together, our data provide further evidence on the beneficial effects of testosterone, which may be useful for future drug development for AD.
authors.affiliation: Laboratory of Neurodegenerative Diseases, Department of Anatomy, LKS Faculty of Medicine, Room L1-49, 21 Sassoon Road, Pokfulam, Hong Kong.
authors.forename: Chi-Fai
authors.initials: CF
authors.lastname: Lau
authors.affiliation: Laboratory of Neurodegenerative Diseases, Department of Anatomy, LKS Faculty of Medicine, Room L1-49, 21 Sassoon Road, Pokfulam, Hong Kong ; State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau.
authors.forename: Yuen-Shan
authors.initials: YS
authors.lastname: Ho
authors.affiliation: Laboratory of Neurodegenerative Diseases, Department of Anatomy, LKS Faculty of Medicine, Room L1-49, 21 Sassoon Road, Pokfulam, Hong Kong ; Institute of Chinese Medicinal Science, University of Macau, Macau.
authors.forename: Clara Hiu-Ling
authors.initials: CH
authors.lastname: Hung
authors.affiliation: Laboratory of Neurodegenerative Diseases, Department of Anatomy, LKS Faculty of Medicine, Room L1-49, 21 Sassoon Road, Pokfulam, Hong Kong ; Department of Psychiatry, LKS Faculty of Medicine, Hong Kong.
authors.forename: Suthicha
authors.identifier: 0000-0002-4976-3514
authors.initials: S
authors.lastname: Wuwongse
authors.affiliation: Laboratory of Neurodegenerative Diseases, Department of Anatomy, LKS Faculty of Medicine, Room L1-49, 21 Sassoon Road, Pokfulam, Hong Kong.
authors.forename: Chun-Hei
authors.initials: CH
authors.lastname: Poon
authors.affiliation: Laboratory of Neurodegenerative Diseases, Department of Anatomy, LKS Faculty of Medicine, Room L1-49, 21 Sassoon Road, Pokfulam, Hong Kong ; Department of Ophthalmology, LKS Faculty of Medicine, Hong Kong.
authors.forename: Kin
authors.initials: K
authors.lastname: Chiu
authors.affiliation: Shenzhen Centre for Disease Control and Prevention, Shenzhen, China.
authors.forename: Xifei
authors.initials: X
authors.lastname: Yang
authors.affiliation: Division of Geriatric, Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, SAR, Hong Kong.
authors.forename: Leung-Wing
authors.identifier: 0000-0002-9066-2811
authors.initials: LW
authors.lastname: Chu
authors.affiliation: Laboratory of Neurodegenerative Diseases, Department of Anatomy, LKS Faculty of Medicine, Room L1-49, 21 Sassoon Road, Pokfulam, Hong Kong ; Research Centre of Heart, Brain, Hormone and Healthy Aging, LKS Faculty of Medicine, Hong Kong ; State Key Laboratory of Brain and Cognitive Sciences, Hong Kong.
authors.forename: Raymond Chuen-Chung
authors.identifier: 0000-0001-8538-7993
authors.initials: RC
authors.lastname: Chang
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D006801:Humans; D000077289:Letrozole; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D009570:Nitriles / Q000008:administration & dosage; D017729:Presynaptic Terminals / Q000187:drug effects; D061251:Primary Cell Culture; D020011:Protective Agents / Q000008:administration & dosage*; D051381:Rats; D013739:Testosterone / Q000008:administration & dosage* / Q000378:metabolism; D014230:Triazoles / Q000008:administration & dosage
chemical_list: D016229:Amyloid beta-Peptides; D009570:Nitriles; D020011:Protective Agents; D014230:Triazoles; D013739:Testosterone; D000077289:Letrozole