A research team led by City of Hope found that the only gene that increases risk for Alzheimer’s disease, ApoE4, may increase risk and COVID-19.
Our study provides a causal link between Alzheimer’s disease risk factor ApoE4 and COVID-19 and explains why some (e.g., ApoE4 carriers) but not all COVID-19 patients show COVID-19 neurological manifestations. Understanding how risk factors for neurodegenerative diseases affect the vulnerability and severity of COVID-19 will help us better address COVID-19 and its potential long-term effects in a variety of ways. patient numbers. “
Yanhong Shi, Ph.D., Director, Stem Cell Biology Department, City of Hope Corresponding Author and Study
At the beginning of the study, the team was interested in the effects of SARS-CoV-2 on the brain. Because COVID-19 patients often lose their taste and smell, the team said the virus had a neurological effect.
The team first created brain cells in the lab using pluripotent stem cells (iPSCs), which are the type of gas cells that can be almost any type of cell. The newly formed neurons and astrocytes, a type of helper cell, were then infected with SARS-CoV-2. They found that both cell types were susceptible to infection.
Next, the team used iPSCs to create brain organoids, which are 3D print models that resemble specific features of the human brain. They created one organoid model containing astrocytes and one without. They infected both types of brain organoids with the virus, and found that those with astrocytes induced SARS-CoV-2 infection.
The team went on to further investigate the effects of ApoE4 on vulnerability to SARS-CoV-2. They did this by generating neurons from “reprogrammed” iPSCs from Alzheimer’s patient cells that contained ApoE4. Using gene editing, the team modified some of the ApoE4 cells that created iPSCs to contain ApoE3, which is a type of gene that is considered neutral. The ApoE3 and ApoE4 iPSCs were then used to generate neurons and astrocytes.
The results were recently published in the journal Stem cells. Both the ApoE4 neurons and astrocytes showed higher vulnerability to SARS-CoV-2 infection compared to the neutral ApoE3 neurons and astrocytes. Furthermore, although the virus damaged both ApoE3 and ApoE4 neurons, it appeared to have a slightly more severe effect on ApoE4 neurons and a much harder effect on ApoE4 astrocytes compared to ApoE3 neurons and astrocytes.
In the latter part of the study, the researchers conducted an experiment to see if the antiviral drug remdesivir inhibits virus infection in neurons and astrocytes. They found that the drug was able to reduce the viral level in astrocytes and prevent cell death. It was also able to save neurons from neurodegeneration.
The next step is to study the effects of the virus to better understand the role of ApoE4 in COVID-19 neurological manifestations. Many people with COVID-19 have recovered, but long-term neurological effects such as headaches can be seen months later.
“COVID-19 is a complex disease, and we are beginning to understand the risk factors involved in revealing the severe form of the disease” said Vaithilingaraja Arumugaswami, Ph.D., a member of UCLA Broad Cell Research Center and corresponding author. “Our cell-based study provides a possible explanation for why people with Alzheimer’s disease are at increased risk of developing more severe COVID-19 symptoms.”