SARS-CoV-2 invades cognitive centers of the brain and induces Alzheimer’s-like neuropathology

  1. Wei-Bin Shen
  2. Montasir Elahi
  3. James Logue
  4. Penghua Yang
  5. Lauren Baracco
  6. E. Albert Reece
  7. Bingbing Wang
  8. Ling Li
  9. Thomas G Blanchard
  10. Zhe Han
  11. Robert A Rissman
  12. Matthew B Frieman
  13. Peixin Yang

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Abstract

The neurotropism of SARS-CoV-2 and the phenotypes of infected neurons are still in debate. Long COVID manifests with “brain diseases” and the cause of these brain dysfunction is mysterious. Here, we analyze 34 age- and underlying disease-matched COVID-19 or non-COVID-19 human brains. SARS-CoV-2 RNA, nucleocapsid, and spike proteins are present in neurons of the cognitive centers of all COVID-19 patients, with its non-structural protein NSF2 detected in adult cases but not in the infant case, indicating viral replications in mature neurons. In adult COVID-19 patients without underlying neurodegeneration, SARS-CoV-2 infection triggers Aβ and p-tau deposition, degenerating neurons, microglia activation, and increased cytokine, in some cases with Aβ plaques and p-tau pretangles. The number of SARS-CoV-2 + cells is higher in patients with neurodegenerative diseases than in those without such conditions. SARS-CoV-2 further activates microglia and induces Aβ and p-tau deposits in non-Alzheimer’s neurodegenerative disease patients. SARS-CoV-2 infects mature neurons derived from inducible pluripotent stem cells from healthy and Alzheimer’s disease (AD) individuals through its receptor ACE2 and facilitator neuropilin-1. SARS-CoV-2 triggers AD-like gene programs in healthy neurons and exacerbates AD neuropathology. An AD infectious etiology gene signature is identified through SARS-CoV-2 infection and silencing the top three downregulated genes in human primary neurons recapitulates the neurodegenerative phenotypes of SARS-CoV-2. Thus, our data suggest that SARS-CoV-2 invades the brain and activates an AD-like program.

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  1. Version published to 10.1101/2022.01.31.478476v3 on bioRxiv
  2. Rapid Reviews Infectious Diseases

    Neville Vassallo

    Review 2: "SARS-CoV-2 invades cognitive centers of the brain and induces Alzheimer’s-like neuropathology"

    This preprint evaluates SARS-CoV-2 neurotropism in COVID-19 infected brains and hypothesizes inductions of Alzheimer’s-like neuropathology upon infection. Reviewers found this study potentially informative with limitations that prevent a strong generalization of authors' results.

  3. Rapid Reviews Infectious Diseases

    Antonio Pisani, Massimiliano Todisco

    Review 1: "SARS-CoV-2 invades cognitive centers of the brain and induces Alzheimer’s-like neuropathology"

    This preprint evaluates SARS-CoV-2 neurotropism in COVID-19 infected brains and hypothesizes inductions of Alzheimer’s-like neuropathology upon infection. Reviewers found this study potentially informative with limitations that prevent a strong generalization of authors' results.

  5. ScreenIT

    SciScore for 10.1101/2022.01.31.478476: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsConsent: All brain tissue is procured, stored, and distributed according to applicable State and Federal guidelines and regulations involving consent, protection of human subjects and donor anonymity.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    The slices were washed with PBS and incubated for 1 h in a biotinylated secondary antibody anti-mouse or rabbit (depending on the host species producing the primary antibodies).
    anti-mouse
    suggested: None
    After blocking with 5% goat serum for 30 minutes overnight incubation with anti Aβ antibody 6E10 were performed.
    anti Aβ
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Stocks were prepared by infection of Vero E6 cells.
    Vero E6
    suggested: RRID:CVCL_XD71)
    Software and Algorithms
    SentencesResources
    The Brain and Tissue Bank is a brain and tissue repository of the NIH NeuroBioBank.
    NeuroBioBank
    suggested: (NIH NeuroBioBank, RRID:SCR_003131)
    HRP intensities and cell counts in 3 different regions (Frontal Cortex, Entorhinal Cortex) in three sections/slices from each group were measured using the ImageJ Fiji platform.
    ImageJ
    suggested: (ImageJ, RRID:SCR_003070)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on page 37. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  6. Version published to 10.1101/2022.01.31.478476v2 on bioRxiv
  7. Version published to 10.1101/2022.01.31.478476v1 on bioRxiv