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

Florent Sauve, Sreekala Nampoothiri, Sophie A. Clarke, Daniela Fernandois, Caio Fernando Ferreira Coêlho, Julie Dewisme, Edouard G. 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 MattotFlorence 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*

*Corresponding author for this work

Abstract

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. 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).

Original languageEnglish
Article number104784
JournalEBioMedicine
Volume96
Pages (from-to)104784
DOIs
Publication statusPublished - 10.2023

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)

Coronavirus related work

  • Research on SARS-CoV-2 / COVID-19

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