The post-coronavirus disease 2019 (COVID-19) condition, commonly known as “long COVID,” is defined by the World Health Organization (WHO) as the continuation or development of new symptoms 3 months after the initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, with these symptoms lasting for at least 2 months with no other explanation [1, 2].
Studies have widely clarified that “long COVID” after discharge from hospital include a mixture of neuropsychiatric complaints, such as defective instant verbal memory and learning, deferred verbal memory difficulties, verbal fluency problems, working memory issues, anxiety, depression, and post-traumatic stress disorder (PTSD) [1, 2]. These complaints can persist for at least 1 year [2]. In some COVID-19 patients, cognitive impairments can even deteriorate over time [2]. Although several pathological mechanisms have been proposed by the author [1], the pathological basis of these symptoms remains unknown.
The hippocampus has imperative functions in spatial and episodic memory [3] as well as learning [4]. In addition, the hippocampus plays an accompanying imperative role in neurogenesis [5] by self-reproducing multipotent adult neural stem cells (NSCs) located in the subgranular zone (SGZ) of the dentate gyrus (DG) [5, 6]. However, the hippocampus, as a vulnerable configuration, can be upset by various neurological and psychiatric disorders [4]. Since the hippocampus is predominantly susceptible to injuries caused by COVID-19 [1], there is increasing evidence indicating the possibility of post-infection memory loss [2, 7].
To explore the etiology of post-infection memory loss in “long COVID,” the role of activated microglial cells has already been highlighted by the author [1, 2]. In this regard, COVID-19 can activate microglia in the hippocampus and induce a central nervous system (CNS) cytokine storm, leading to loss of hippocampal neurogenesis [1, 2]. The activation of microglia in the hippocampus of deceased patients with “long COVID” and cognitive impairments as well as mild COVID-19 animal model was shown to be due to elevated levels of C–C motif chemokine ligand 11 (CCL11), leading to inhibited neurogenesis [8]. Activated pro-inflammatory microglia through inflammatory mediators, such as tumor necrosis factor alpha (TNF-α), interleukin-1 alpha (IL-1α), complement component 1q, and IL-1β, can then activate pro-inflammatory astrocytes and fuel a secondary inflammatory response [1, 2]. Consequently, this disturbs hippocampal neuronal cells, leading to memory difficulties and neuronal apoptosis. These pathological pathways can explain the potential damaging consequences of SARS-CoV-2-linked glial activation, neuroinflammation, and apoptosis [1, 2]. This can eventually disturb hippocampal neuronal cells, leading to memory difficulties and neuronal apoptosis [1, 2].
Therefore, the reduced neurogenesis, which was shown in the COVID-19 group [9], could be due to microglial activation and the subsequent production of inflammatory cytokines, such as TNF-α, IL-6, and IL-1β, causing neuroinflammation and the resultant impaired neurogenesis [1, 2, 9]. This eventually results in cognitive decline due to the destruction of spatial memory and learning [1, 2, 9]. These implications on the hippocampus, especially the loss of hippocampal neurogenesis in the brains of COVID-19 patients, elucidate learning, memory, and executive impairments in COVID-19 patients compared with uninfected healthy controls [10].
As a result, memory loss in patients with “long COVID” can be due to reduced hippocampal neurogenesis. This negative consequence is mediated by inflammatory mediators secreted by activated microglia in the hippocampus, which can induce a cytokine storm in the CNS. This highlights the specific susceptibility of the hippocampus to neuroinflammation. A better perspective of the cellular features of COVID-19 brain injury could assist in interventions to ease long-term neuropsychiatric complaints. In addition, the neuropathology of COVID-19 may provide a replica for decoding the neurodegenerative mechanisms related to neuroinflammation in other brain diseases and for developing new therapeutic strategies.
Acknowledgements
The author would like to express his honest gratitude and high respect for the lifetime support of his father, Mohammad Nouraeinejad.
Author contributions
The work has all been done by AN.
Funding
The author received no financial support for the research, authorship, and/or publication of this article.
Availability of data and materials
No applicable.
Code availability
No applicable.
Declarations
Conflict of interest
The author declares no conflict of interest.
Ethical approval
No applicable.
Consent to participate
No applicable.
Consent for publication
The author has full right to publish this manuscript.
References
- 1.Nouraeinejad A. The pathological mechanisms underlying brain fog or cognitive impairment in long COVID. Int J Neurosci. 2022 doi: 10.1080/00207454.2022.2150845. [DOI] [PubMed] [Google Scholar]
- 2.Nouraeinejad A. Brain fog as a long-term sequela of COVID-19. SN Compr Clin Med. 2023;5(1):9. doi: 10.1007/s42399-022-01352-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Dekeyzer S, De Kock I, Nikoubashman O, VandenBossche S, Van Eetvelde R, De Groote J, Acou M, Wiesmann M, Deblaere K, Achten E. "Unforgettable" - a pictorial essay on anatomy and pathology of the hippocampus. Insights Imaging. 2017;8(2):199–212. doi: 10.1007/s13244-016-0541-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Anand KS, Dhikav V. Hippocampus in health and disease: an overview. Ann Indian Acad Neurol. 2012;15(4):239–246. doi: 10.4103/0972-2327.104323. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Mu Y, Gage FH. Adult hippocampal neurogenesis and its role in Alzheimer's disease. Mol Neurodegener. 2011;22(6):85. doi: 10.1186/1750-1326-6-85. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Bonaguidi MA, Wheeler MA, Shapiro JS, Stadel RP, Sun GJ, Ming GL, Song H. In vivo clonal analysis reveals self-renewing and multipotent adult neural stem cell characteristics. Cell. 2011;145:1142–1155. doi: 10.1016/j.cell.2011.05.024. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Ritchie K, Chan D, Watermeyer T. The cognitive consequences of the COVID-19 epidemic: collateral damage? Brain Commun. 2020;2(2):fcaa069. doi: 10.1093/braincomms/fcaa069. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Fernández-Castañeda A, Lu P, Geraghty AC, et al. Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation. Cell. 2022;185(14):2452.e16–2468.e16. doi: 10.1016/j.cell.2022.06.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Bayat AH, Azimi H, HassaniMoghaddam M, Ebrahimi V, Fathi M, Vakili K, Mahmoudiasl GR, Forouzesh M, Boroujeni ME, Nariman Z, Abbaszadeh HA, Aryan A, Aliaghaei A, Abdollahifar MA. COVID-19 causes neuronal degeneration and reduces neurogenesis in human hippocampus. Apoptosis. 2022;27(11–12):852–868. doi: 10.1007/s10495-022-01754-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Soung AL, Vanderheiden A, Nordvig AS, Sissoko CA, Canoll P, Mariani MB, Jiang X, Bricker T, Rosoklija GB, Arango V, Underwood M, Mann JJ, Dwork AJ, Goldman JE, Boon ACM, Boldrini M, Klein RS. COVID-19 induces CNS cytokine expression and loss of hippocampal neurogenesis. Brain. 2022;145(12):4193–4201. doi: 10.1093/brain/awac270. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
No applicable.
No applicable.