Reactive Astrocytosis-A Potential Contributor to Increased Suicide in Long COVID-19 Patients?

Alessandra Costanza^{1

2

3

4}, Andrea Amerio^{5

6}, Andrea Aguglia^{5

6}, Martina Rossi⁴, Alberto Parise⁷, Luca Magnani⁸, Gianluca Serafini^{5

6}, Mario Amore^{5

6}, Daniel Martins^{9

10}, Khoa D Nguyen^{11

12}

Affiliations

¹ Department of Psychiatry, Faculty of Medicine, University of Geneva (UNIGE), 24 Rue du Général-Dufour, 1211 Geneva, Switzerland.
² Department of Psychiatry, Faculty of Biomedical Sciences, University of Italian Switzerland (USI), Via Giuseppe Buffi 13, 6900 Lugano, Switzerland.
³ Department of Psychiatry, Adult Psychiatry Service, University Hospitals of Geneva (HUG), Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland.
⁴ "Nel Chiostro", Medical and Study Center, Via Camillo Leone 29, 13100 Vercelli, Italy.
⁵ Section of Psychiatry, Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Via Balbi, 5, 16132 Genoa, Italy.
⁶ IRCCS Polyclinic Hospital San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy.
⁷ Geriatric-Rehabilitation Department, University Hospital of Parma, 43126 Parma, Italy.
⁸ Department of Psychiatry, San Maurizio Hospital of Bolzano, Via Lorenz Böhler, 5, 39100 Bolzano, Italy.
⁹ Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience (IoPPN)-King's College London (KCL), Strand Campus, London WC2R 2LS, UK.
¹⁰ NIHR Maudesley BRC, 16 De Crespigny Park, SE5 8AF South London and Maudesley NHS Trust, Denmark Hill, London SE5 8AZ, UK.
¹¹ Program in Immunology, Stanford University, 450 Jane Stanford Way, Stanford, CA 94305, USA.
¹² Department of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong SAR, China.

PMID: 39451987
PMCID: PMC11505806
DOI: 10.3390/brainsci14100973

Review

Reactive Astrocytosis-A Potential Contributor to Increased Suicide in Long COVID-19 Patients?

Alessandra Costanza et al. Brain Sci. 2024.

. 2024 Sep 27;14(10):973.

doi: 10.3390/brainsci14100973.

Authors

Affiliations

¹ Department of Psychiatry, Faculty of Medicine, University of Geneva (UNIGE), 24 Rue du Général-Dufour, 1211 Geneva, Switzerland.
² Department of Psychiatry, Faculty of Biomedical Sciences, University of Italian Switzerland (USI), Via Giuseppe Buffi 13, 6900 Lugano, Switzerland.
³ Department of Psychiatry, Adult Psychiatry Service, University Hospitals of Geneva (HUG), Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland.
⁴ "Nel Chiostro", Medical and Study Center, Via Camillo Leone 29, 13100 Vercelli, Italy.
⁵ Section of Psychiatry, Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Via Balbi, 5, 16132 Genoa, Italy.
⁶ IRCCS Polyclinic Hospital San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy.
⁷ Geriatric-Rehabilitation Department, University Hospital of Parma, 43126 Parma, Italy.
⁸ Department of Psychiatry, San Maurizio Hospital of Bolzano, Via Lorenz Böhler, 5, 39100 Bolzano, Italy.
⁹ Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience (IoPPN)-King's College London (KCL), Strand Campus, London WC2R 2LS, UK.
¹⁰ NIHR Maudesley BRC, 16 De Crespigny Park, SE5 8AF South London and Maudesley NHS Trust, Denmark Hill, London SE5 8AZ, UK.
¹¹ Program in Immunology, Stanford University, 450 Jane Stanford Way, Stanford, CA 94305, USA.
¹² Department of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong SAR, China.

PMID: 39451987
PMCID: PMC11505806
DOI: 10.3390/brainsci14100973

Abstract

Background: Long COVID-19 is an emerging chronic illness of significant public health concern due to a myriad of neuropsychiatric sequelae, including increased suicidal ideation (SI) and behavior (SB).

Methods: This review provides a concise synthesis of clinical evidence that points toward the dysfunction of astrocytes, the most abundant glial cell type in the central nervous system, as a potential shared pathology between SI/SB and COVID-19.

Results: Depression, a suicide risk factor, and SI/SB were both associated with reduced frequencies of various astrocyte subsets and complex proteomic/transcriptional changes of astrocyte-related markers in a brain-region-specific manner. Astrocyte-related circulating markers were increased in depressed subjects and, to a less consistent extent, in COVID-19 patients. Furthermore, reactive astrocytosis was observed in subjects with SI/SB and those with COVID-19.

Conclusions: Astrocyte dysfunctions occurred in depression, SI/SB, and COVID-19. Reactive-astrocyte-mediated loss of the blood-brain barrier (BBB) integrity and subsequent neuroinflammation-a factor previously linked to SI/SB development-might contribute to increased suicide in individuals with long COVID-19. As such, the formulation of new therapeutic strategies to restore astrocyte homeostasis, enhance BBB integrity, and mitigate neuroinflammation may reduce SI/SB-associated neuropsychiatric manifestations among long COVID-19 patients.

Keywords: astrocytes; blood–brain barrier; depression; long COVID-19; neuroinflammation; reactive astrocytosis; suicidal behavior; suicidal ideation.

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Conflict of interest statement

K.D.N. is the scientific founder of Tranquis Therapeutics, a biotechnology company that develops novel treatments for neuroinflammatory and neurodegenerative diseases. K.D.N. is also a scientific advisor for Tochikunda, a biotechnology company that develops SARS-CoV-2 diagnostic devices. However, this had no impact on the interpretation of data, the writing of this review, or its publication. All other authors declare no conflicts of interest and that they have no commercial associations (e.g., consultancies, stock ownership, equity interest, patent/licensing arrangement, etc.) that might pose a conflict of interest in connection with the submitted article.

Figures

**Figure 1**
Astrocyte perturbations in individuals affected by depression or suicidal behavior/suicidal ideation. Changes in astrocyte abundance and astrocyte-related gene/protein expression were observed in both depressed subjects (**left**) and those with suicidal ideation/suicidal behavior (SI/SB) (**right**). Furthermore, depressed patients showed alterations in circulating levels of astrocyte-related markers, while subjects with SI/SB experienced reactive astrocytosis. Abbreviations: ALDH1L1: Aldehyde Dehydrogenase 1 Family Member L1; AQP4: Aquaporin 4; CNS: Central Nervous System; CSF: Cerebrospinal Fluid; EV: Extracellular Vesicles; GFAP: Glial Fibrillary Acidic Protein; GJA1: Gap Junction Protein Alpha 1; GJB6: Gap Junction Protein Beta 6; GLUL: Glutamate-Ammonia Ligase; GLUS: Glutamine Synthetase; KCNJ10: Potassium Inwardly Rectifying Channel Subfamily J Member 10; S100B: S100 Calcium-Binding Protein B; SLC1A1/2/3: Solute Carrier Family 1 Member 1/2/3; SOX9: SRY-Box Transcription Factor 9; TrkB1: Tropomyosin Receptor Kinase B1.

**Figure 2**
Astrocyte dysfunction and their possible involvement in suicide development during COVID-19 pathogenesis. COVID-19 is characterized by various astrocyte-related dysfunctions, including reactive astrocytosis and potential changes in the circulating astrocyte-related markers (S100B and/or GFAP) in different phases of COVID-19 (acute vs. long). Importantly, these astrocyte abnormalities might represent an overlapping pathology between suicide and long COVID-19 via chronic reactive astrocytosis-mediated disruption of the blood–brain barrier, which promotes neuroinflammation and subsequently heightens the prevalence of SI/SB.

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References

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Reactive Astrocytosis-A Potential Contributor to Increased Suicide in Long COVID-19 Patients?

Affiliations

Reactive Astrocytosis-A Potential Contributor to Increased Suicide in Long COVID-19 Patients?

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

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Research Materials