cover image: Long-COVID cognitive impairments and reproductive hormone deficits in men may stem from GnRH neuronal death

Long-COVID cognitive impairments and reproductive hormone deficits in men may stem from GnRH neuronal death

1 Oct 2023

Background We have recently demonstrated a causal link between loss of gonadotropin-releasing hormone (GnRH), the master molecule regulating reproduction, and cognitive deficits during pathological aging, including Down syndrome and Alzheimer's disease. Olfactory and cognitive alterations, which persist in some COVID-19 patients, and long-term hypotestosteronaemia in SARS-CoV-2-infected men are also reminiscent of the consequences of deficient GnRH, suggesting that GnRH system neuroinvasion could underlie certain post-COVID symptoms and thus lead to accelerated or exacerbated cognitive decline. Methods We explored the hormonal profile of COVID-19 patients and targets of SARS-CoV-2 infection in post-mortem patient brains and human fetal tissue. Findings We found that persistent hypotestosteronaemia in some men could indeed be of hypothalamic origin, favouring post-COVID cognitive or neurological symptoms, and that changes in testosterone levels and body weight over time were inversely correlated. Infection of olfactory sensory neurons and multifunctional hypothalamic glia called tanycytes highlighted at least two viable neuroinvasion routes. Furthermore, GnRH neurons themselves were dying in all patient brains studied, dramatically reducing GnRH expression. Human fetal olfactory and vomeronasal epithelia, from which GnRH neurons arise, and fetal GnRH neurons also appeared susceptible to infection. Interpretation Putative GnRH neuron and tanycyte dysfunction following SARS-CoV-2 neuroinvasion could be responsible for serious reproductive, metabolic, and mental health consequences in long-COVID and lead to an increased risk of neurodevelopmental and neurodegenerative pathologies over time in all age groups.

Authors

Florent Sauve, Sreekala Nampoothiri, Sophie Clarke, Daniela Fernandois, Caio Fernando Ferreira Coêlho, Julie Dewisme, Edouard Mills, Gaetan Ternier, Ludovica Cotellessa, Cristina Iglesias-Garcia, Helge Mueller-Fielitz, Thibaud Lebouvier, Romain Perbet, Vincent Florent, Marc Baroncini, Ariane Sharif, June Ereño-Orbea, Maria Mercado-Gómez, Asis Palazon, Virginie Mattot, Florence Pasquier, Sophie Catteau-Jonard, Maria Martinez-Chantar, Erik Hrabovszky, Mercé Jourdain, Dominique Deplanque, Annamaria Morelli, Giulia Guarnieri, Laurent Storme, Cyril Robil, François Trottein, Ruben Nogueiras, Markus Schwaninger, Pascal Pigny, Julien Poissy, Konstantina Chachlaki, Claude-Alain Maurage, Paolo Giacobini, Waljit Dhillo, S. Rasika, Vincent Prevot

Related Organizations

European Union
Imperial College London
University of Florence
Bibliographic Reference
Florent Sauve, Sreekala Nampoothiri, Sophie Clarke, Daniela Fernandois, Caio Fernando Ferreira Coêlho, et al.. Long-COVID cognitive impairments and reproductive hormone deficits in men may stem from GnRH neuronal death. EBioMedicine, 2023, 96 (2), pp.104784. ⟨10.1016/j.ebiom.2023.104784⟩. ⟨inserm-04252389⟩
DOI
https://doi.org/10.1016/j.ebiom.2023.104784
Funding
European Research Council (ERC) grant agreements No 810331, No 725149, No 804236, the European Union Horizon 2020 research and innovation program No 847941, the Fondation pour la Recherche Médicale (FRM) and the Agence Nationale de la Recherche en Santé (ANRS) No ECTZ200878 Long Covid 2021 ANRS0167 SIGNAL, Agence Nationale de la recherche (ANR) grant agreements No ANR-19-CE16-0021-02, No ANR-11-LABEX-0009, No. ANR-10-LABEX-0046, No. ANR-16-IDEX-0004, Inserm Cross-Cutting Scientific Program HuDeCA, the CHU Lille Bonus H, the UK Medical Research Council (MRC) and National Institute of Health and care Research (NIHR).
HAL Collection
['INSERM - Institut national de la santé et de la recherche médicale', 'Institut Pasteur RIIP (Réseau International)', 'CNRS - Centre national de la recherche scientifique', 'Université de Lille', "Centre d'Infection et d'Immunité de Lille", 'ANR', 'Fondation pour la Recherche Médicale']
HAL Identifier
4252389
Institution
['Institut National de la Santé et de la Recherche Médicale', 'Centre Hospitalier Régional Universitaire [Lille]', 'Imperial College London', 'Universidade de Santiago de Compostela [Spain]', 'Universität zu Lübeck = University of Lübeck [Lübeck]', 'Institut Pasteur de Lille', 'Università degli Studi di Firenze = University of Florence', 'Hôpital Jeanne de Flandre [Lille]']
Laboratory
['Lille Neurosciences & Cognition - U 1172', 'Recherche translationnelle sur le diabète - U 1190', "Centre d'Investigation Clinique - Innovation Technologique de Lille - CIC 1403 - CIC 9301", 'Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204']
Published in
France

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