In a recent study published on bioRxiv* preprint server, researchers assessed the neurotropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its impact on patients with coronavirus disease 2019 (COVID-19) with and without neurological disorders as Alzheimer’s disease.
The ongoing COVID-19 pandemic has resulted in over 380 million confirmed SARS-CoV-2 infections worldwide. In addition to respiratory manifestations, SARS-CoV-2 also causes neurological abnormalities with an occurrence rate of 85% in people with Alzheimer’s.
Most patients with COVID-19 present with neurological symptoms such as headache, anosmia and hypogeusia before the manifestation of respiratory symptoms. Additionally, the long-term sequelae of COVID-19 range from mild cognitive impairment to dementia.
A recent study demonstrated the presence of SARS-CoV-2 in the olfactory mucosa and its neuronal projections of a patient infected with COVID-19. Furthermore, additional pathways of SARS-CoV-2 entry have been proposed, for example via the compromised blood-brain barrier (BBB) in conditions such as autism and Alzheimer’s disease, but a sufficient evidence of infected immune cells remains absent.
Taken together, although the major factors promoting SARS-CoV-2 cellular entry have been found in neurons, sufficient information regarding the phenotypes of infected neurons and the neurotropism of SARS-CoV-2 is not yet available.
About the study
In the current study, the team of researchers investigated the potential neurotropic characteristics of SARS-CoV-2 in COVID-19 patients with Alzheimer’s disease, autism, dementia, and those without any comorbid conditions. The control group for the study consisted of non-COVID patients with the aforementioned comorbidities.
Immunohistological staining and double immunohistological labeling (DAB) of SARS-CoV-2 spike (S) protein in brain tissues of age-matched study and control groups were performed to determine the presence of the SARS-CoV-2 in brain regions. Furthermore, the development of Alzheimer-like phenotype and exacerbation of Alzheimer-like phenotypes in SARS-CoV-2 were determined using β-amyloid (Aβ) and phospho-tau (pTau) immunohistochemistry. and immunofluorescence analysis with thioflavin staining of Aβ of brain tissue samples. SARS-CoV-2 genomic ribonucleic acid (RNA) in samples was analyzed using RNAscope on the spot hybridization.
The results indicated that SARS-CoV-2 invaded the lower frontal cortices of five COVID-19 patients: one subject with frontotemporal dementia (FTD), one with Alzheimer’s disease, two with autism and one. healthy subject without any comorbid condition by infecting neurons and several other cells of the cerebral cortex.
The cortices of the two young autistic COVID-19 patients demonstrated the presence of p-Tau tangles. Manifestations such as cellular Aβ accumulation and plaque formation, neuroinflammation, tauopathy, senescence, ferroptosis, necroptosis and apoptosis in COVID-19 patients indicated that SARS-CoV-2 ameliorates or induces neuropathology similar to Alzheimer’s disease.
Mature SARS-CoV-2 infected neurons were derived from inducible pluripotent stem cells (iPSCs) of age-matched healthy COVID-19 patients and those with Alzheimer’s disease via the enzyme receptor converting angiotensin 2 (ACE2) and a facilitator named neuropilin-1 (NRP1), but SARS-CoV-2 did not infect immature neurons.
Furthermore, SARS-CoV-2 triggered an Alzheimer’s-like cellular program in iPSC-derived neurons from healthy COVID-19 patients and enhanced Alzheimer’s phenotypes in neurons from iPSCs from patients with AD. Alzheimer’s.
A list of 24 genes was identified from groups infected with simulated and healthy neurons infected with Alzheimer’s SARS-CoV-2, which activated infection pathways induced by viruses and bacteria. In neurons of Alzheimer’s disease patients infected with COVID-19, SARS-CoV-2 enhanced and reduced the expression of 25 up-regulated genes and 34 down-regulated genes, respectively, by several-fold. Thus, SARS-CoV-2 worsens Alzheimer’s conditions through altered gene expression, elevated neuroinflammation, and other neurological processes in neurons of Alzheimer’s patients.
Moreover, the silencing of the three main underexpressed genes in human primary neurons, named CryAA2, PSG6 and GJA8, by SARS-CoV-2 resulted in the conversion of healthy human neurons into Alzheimer-like neurons during COVID-19. .
Study findings showed that SARS-CoV-2 penetrated the cognitive centers of COVID-19 patients, resulting in Alzheimer’s-like phenotypes in those without any underlying conditions, and exacerbated the neuropathology of Alzheimer’s in patients with Alzheimer’s and autism. Furthermore, SARS-CoV-2-infected neurons derived from iPSCs demonstrated the pathological hallmarks of neurological disorders, including neurotropism and induction or amelioration of Alzheimer’s disease in COVID patients and convalescents. -19. The 24 overlapping genes identified from Alzheimer’s neurons without SARS-CoV-2 and healthy neurons with SARS-CoV-2 were potential mediators of infectious Alzheimer’s etiology in SARS-CoV infection -2.
BBB leakage is thought to be the primary central nervous system (CNS) entry route for SARS-CoV-2 in autistic patients, as no evidence of SARS-CoV-2 infected immune cell infiltration in autistic brains was observed in the current study. The study findings were in line with that of previous studies suggesting manifestations of neurodegenerative characteristics in the brain of COVID-19 patients. Further research is needed to illustrate the mechanism by which SARS-CoV-2 caused Alzheimer-like phenotypes.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be considered conclusive, guide clinical practice/health-related behaviors, or treated as established information.