title: Sex hormone-related neurosteroids differentially rescue bioenergetic deficits induced by amyloid-β or hyperphosphorylated tau protein.
abstract: Alzheimer's disease (AD) is an age-related neurodegenerative disease marked by a progressive cognitive decline. Metabolic impairments are common hallmarks of AD, and amyloid-β (Aβ) peptide and hyperphosphorylated tau protein--the two foremost histopathological signs of AD--have been implicated in mitochondrial dysfunction. Neurosteroids have recently shown promise in alleviating cognitive and neuronal sequelae of AD. The present study evaluates the impact of neurosteroids belonging to the sex hormone family (progesterone, estradiol, estrone, testosterone, 3α-androstanediol) on mitochondrial dysfunction in cellular models of AD: human neuroblastoma cells (SH-SY5Y) stably transfected with constructs encoding (1) the human amyloid precursor protein (APP) resulting in overexpression of APP and Aβ, (2) wild-type tau (wtTau), and (3) mutant tau (P301L), that induces abnormal tau hyperphosphorylation. We show that while APP and P301L cells both display a drop in ATP levels, they present distinct mitochondrial impairments with regard to their bioenergetic profiles. The P301L cells presented a decreased maximal respiration and spare respiratory capacity, while APP cells exhibited, in addition, a decrease in basal respiration, ATP turnover, and glycolytic reserve. All neurosteroids showed beneficial effects on ATP production and mitochondrial membrane potential in APP/Aβ overexpressing cells while only progesterone and estradiol increased ATP levels in mutant tau cells. Of note, testosterone was more efficient in alleviating Aβ-induced mitochondrial deficits, while progesterone and estrogen were the most effective neurosteroids in our model of AD-related tauopathy. Our findings lend further support to the neuroprotective effects of neurosteroids in AD and may open new avenues for the development of gender-specific therapeutic approaches in AD.
authors.affiliation: Neurobiology Laboratory for Brain Aging and Mental Health, Transfaculty Research Platform, Molecular and Cognitive Neuroscience, University of Basel, Wilhelm Klein-Str. 27, 4012, Basel, Switzerland.|Psychiatric University Clinics, University of Basel, Wilhelm Klein-Str. 27, 4012, Basel, Switzerland.|Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Bâtiment 3 de la Faculté de Médecine, 11 rue Humann, 67 000, Strasbourg, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Grimm
authors.affiliation: Neurobiology Laboratory for Brain Aging and Mental Health, Transfaculty Research Platform, Molecular and Cognitive Neuroscience, University of Basel, Wilhelm Klein-Str. 27, 4012, Basel, Switzerland.|Psychiatric University Clinics, University of Basel, Wilhelm Klein-Str. 27, 4012, Basel, Switzerland.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Biliouris
authors.affiliation: Psychiatric University Clinics, University of Basel, Wilhelm Klein-Str. 27, 4012, Basel, Switzerland.
authors.forename: Undine E
authors.initials: UE
authors.lastname: Lang
authors.affiliation: Clem Jones Centre for Ageing Dementia Research (CJCADR), Queensland Brain Institute (QBI), The University of Queensland, Brisbane, 4072, QLD, Australia.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Götz
authors.affiliation: Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Bâtiment 3 de la Faculté de Médecine, 11 rue Humann, 67 000, Strasbourg, France.
authors.forename: Ayikoe Guy
authors.initials: AG
authors.lastname: Mensah-Nyagan
authors.affiliation: Neurobiology Laboratory for Brain Aging and Mental Health, Transfaculty Research Platform, Molecular and Cognitive Neuroscience, University of Basel, Wilhelm Klein-Str. 27, 4012, Basel, Switzerland. anne.eckert@upkbs.ch.|Psychiatric University Clinics, University of Basel, Wilhelm Klein-Str. 27, 4012, Basel, Switzerland. anne.eckert@upkbs.ch.
authors.forename: Anne
authors.initials: A
authors.lastname: Eckert
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004734:Energy Metabolism; D012739:Gonadal Steroid Hormones / Q000378:metabolism*; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010766:Phosphorylation; D017354:Point Mutation; D015854:Up-Regulation; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D012739:Gonadal Steroid Hormones; D018377:Neurotransmitter Agents; D016875:tau Proteins; D000255:Adenosine Triphosphate
keywords: Amyloid-β peptide; Bioenergetics; Mitochondria; Neurosteroids; Tau protein