Project Team

Benjamin Readhead, PhD: Research Associate Professor, ASU-Banner Neurodegenerative Disease Research Center, Arizona State University

Elaine Lim, PhD: Assistant Professor, Genomics and Computational Biology, UMass Chan Medical School

Rigel Chan, PhD: Assistant Professor in the Department of Neurology, UMass Chan Medical School

Fiachra Humphries, PhD: Assistant Professor of Medicine Division of Innate Immunity, UMass Chan Medical School


Katherine Fitzgerald, PhD: Professor and Vice Chair of Medicine, Chief of the Division of Innate Immunity, and the Worcester Foundation in Biomedical Sciences Research, UMass Chan Medical School

George Church, PhD: Professor of Genetics at Harvard Medical School and Professor of Health Sciences and Technology at Harvard and the Massachusetts Institute of Technology (MIT)

Project summary:

(From left,) Project team members Dr. Rigel Chan, Dr. Elaine Lim, and Dr. Fiachra Humphries

The project will determine if live SARS-CoV-2 infection of human brain cell models leads to protein formation and gene changes connected to Alzheimer’s disease, Parkinson’s disease, or TDP43-associated dementia. A second series of experiments is measuring the detrimental impact of SARS-CoV-2 spike protein on brain cells such neurons, microglia, and oligodendrocytes. Advanced sequencing methods are being used to document gene changes and immune pathway alterations perturbed by SARS-CoV-2 or spike protein exposure. The team will also use the brain cell models to explore how co-infection of SARS-CoV-2 and other common viruses (e.g. herpesviruses) may exacerbate the formation of neurodegenerative disease markers.

Project background:

SARS-CoV-2 infection is directly connected to the development of neurodegenerative disease. For example, one team found that older adults had a significantly increased risk for a new Alzheimer’s diagnosis within 360 days after acute COVID-19. A separate autopsy study demonstrated increased amyloid beta plaque deposition in brain tissue obtained from severely ill individuals hospitalized with COVID-19 who were younger than 60 years old. Alzheimer’s disease amyloid ‘plaque’ has also been shown to function as an antimicrobial peptide that forms as part of the host innate immune response toward pathogens capable of infecting brain tissue. In a series experiments, a Harvard team demonstrated amyloid plaque accumulation in response to bacteria, fungi and viruses. Thus, SARS-CoV-2 persistence in the central nervous system—or reactivation of other pathogens such as herpesviruses after COVID-19—might contribute to an increase in both short-term and long-term risk for Alzheimer’s disease or other neurodegenerative problems.

The current project draws on this research to determine if the SARS-CoV-2 virus can seed Alzheimer’s-associated proteins such as amyloid plaque and Tau. To do this, the team will use brain cell models (called cerebral organoids) that they previously used to study the impact of herpes simplex virus 1 and cytomegalovirus on neurodegenerative diseases. Neuronal death, microglial immune cell activation, and other parameters will be measured in the cerebral organoid models after SARS-CoV-2 infection or spike protein expression. The team will also inhibit or activate immune pathways impacted by infection to understand if pathway modulation can lead to reversal of disease-associated pathology. Identification of these changes or other genes altered by SARS-CoV-2 infection/spike could allow the team to identify therapeutic targets to reverse neuroinflammation-induced neurodegenerative pathology.