Blood-brain barrier penetration of non-replicating SARS-CoV-2 and S1 variants of concern induce neuroinflammation which is accentuated in a mouse model of Alzheimer's disease

Michelle A Erickson; Aric F Logsdon; Elizabeth M Rhea; Kim M Hansen; Sarah J Holden; William A Banks; Jessica L Smith; Cody German; Susan A Farr; John E Morley; Riley R Weaver; Alec J Hirsch; Andrej Kovac; Eva Kontsekova; Kristen K Baumann; Mohamed A Omer; Jacob Raber

doi:10.1016/j.bbi.2023.01.010

Blood-brain barrier penetration of non-replicating SARS-CoV-2 and S1 variants of concern induce neuroinflammation which is accentuated in a mouse model of Alzheimer's disease

Brain Behav Immun. 2023 Mar:109:251-268. doi: 10.1016/j.bbi.2023.01.010. Epub 2023 Jan 20.

Authors

Michelle A Erickson¹, Aric F Logsdon¹, Elizabeth M Rhea¹, Kim M Hansen², Sarah J Holden³, William A Banks⁴, Jessica L Smith⁵, Cody German⁵, Susan A Farr⁶, John E Morley⁷, Riley R Weaver², Alec J Hirsch⁵, Andrej Kovac⁸, Eva Kontsekova⁸, Kristen K Baumann², Mohamed A Omer², Jacob Raber⁹

Affiliations

¹ Geriatrics Research Educational and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, School of Medicine, University of Washington, Seattle, WA, USA.
² Geriatrics Research Educational and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA.
³ Department of Behavioral Neurosciences, Oregon Health and Science University, Portland, OR, USA.
⁴ Geriatrics Research Educational and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, School of Medicine, University of Washington, Seattle, WA, USA. Electronic address: wabanks1@uw.edu.
⁵ The Vaccine and Gene Therapy Institute, Oregon Health and Sciences University, Beaverton, OR, USA; Division of Pathobiology and Immunology Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, OR, USA.
⁶ Saint Louis Veterans Affairs Medical Center, Research Service, St. Louis, MO, USA; Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, MO, USA.
⁷ Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, MO, USA.
⁸ Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovak Republic.
⁹ Department of Behavioral Neurosciences, Oregon Health and Science University, Portland, OR, USA; Department of Neurology, Psychiatry, and Radiation Medicine, Division of Neuroscience, Departments of Neurology and Radiation Medicine, Oregon National Primate Research Center, Oregon Health Sciences University, Portland, OR, USA.

Abstract

COVID-19 and especially Long COVID are associated with severe CNS symptoms and may place persons at risk to develop long-term cognitive impairments. Here, we show that two non-infective models of SARS-CoV-2 can cross the blood-brain barrier (BBB) and induce neuroinflammation, a major mechanism underpinning CNS and cognitive impairments, even in the absence of productive infection. The viral models cross the BBB by the mechanism of adsorptive transcytosis with the sugar N-acetylglucosamine being key. The delta and omicron variants cross the BB B faster than the other variants of concern, with peripheral tissue uptake rates also differing for the variants. Neuroinflammation induced by icv injection of S1 protein was greatly enhanced in young and especially in aged SAMP8 mice, a model of Alzheimer's disease, whereas sex and obesity had little effect.

Keywords: Aging; Alzheimer's disease; Blood–brain barrier; COVID-19; Glycoprotein; Microglia; Neuroinflammation; Obesity; SARS-CoV-2; Virus.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Alzheimer Disease* / metabolism
Animals
Blood-Brain Barrier / metabolism
COVID-19* / complications
Humans
Mice
Neuroinflammatory Diseases
Post-Acute COVID-19 Syndrome
SARS-CoV-2

Supplementary concepts

SARS-CoV-2 variants

Abstract

Publication types

MeSH terms

Supplementary concepts

Grants and funding