A new Yale study has found a promising target for treating the brain fog that can follow COVID-19 and offers new insight into a hypothesis about the origin of Alzheimer’s disease.

One of the hallmarks of Alzheimer’s disease is the presence of plaque formed by the buildup of amyloid beta peptides (short chains of amino acids) in and around brain cells. Some researchers suspect that amyloid beta, which is structurally similar to antimicrobial peptides, protects the brain against bacteria, viruses, parasites, and fungal infections. Because the blood-brain barrier tends to lose its integrity in Alzheimer’s disease patients, the accumulation of amyloid beta might be a signal that pathogens are infiltrating the brain.

In a new study published in Science Advances, Yale researchers investigated whether infection by SARS-CoV-2—the virus that causes COVID-19—can trigger Alzheimer’s disease-like amyloid beta buildup, leading to neurological impairments like brain fog.

“There is growing evidence linking COVID-19 and brain fog, a commonly reported symptom following infection,” says senior author Brian Hafler, MD, PhD, associate professor of ophthalmology and visual science at Yale School of Medicine. Brain fog, or the difficulty in thinking or concentrating, is a symptom that Alzheimer’s disease patients may also experience. “While the mechanisms of brain fog after COVID-19 are not fully understood, scientists have found that SARS-CoV-2 can induce amyloid beta accumulation in the central nervous system.”

Using the retina to study the brain
To recapitulate the genetic complexities of Alzheimer’s disease, Hafler and his team used donated retinal tissue and grew retinal organoids, mini organs made out of human stem cells that have been directed to become retinal tissue. In this case, the retinal organoids mimicked Alzheimer's disease features, such as having genetic mutations that cause them to produce more amyloid beta than normal tissues.

“We think that there are a lot of advantages of the human retinal organoids over animals because of the human-specific aspect of the model. We're not dealing with any species mismatch,” says Hafler.

The scientists first confirmed that the accumulation of amyloid beta typically found in the brains of people with Alzheimer’s disease was also found in their retinal tissue. The retina, therefore, provides an accessible and non-invasive window to study what is happening in the central nervous system, Hafler says.

The team also found evidence that SARS-CoV-2 can enter the cells of the retina.

To do this, they assessed protein production across the different cell types of retinal tissue by measuring RNA in individual cell nuclei. They focused specifically on NRP1 (neuropilin-1) and ACE2 (angiotensin-converting enzyme 2) proteins, which evidence suggests SARS-CoV-2 uses to enter neurons.

In retinal tissue from people who had COVID-19, they found NRP1 in neurons and another type of central nervous system cell called glia, suggesting that the eye does have a mechanism for viral entry.

With these findings in hand, the researchers then exposed organoids to the SARS-CoV-2 spike protein, the part of the virus essential for entering human cells. They found that amyloid beta levels in the organoids increased once the spike protein entered the cells.

Further, human retinal tissues collected from patients with COVID-19 but without any history of dementia also showed higher amyloid beta accumulation than that found in healthy individuals, to a degree similar to what the researchers found in retinal tissue from people with Alzheimer’s disease.

This accumulation of amyloid beta was reversed, however, when the scientists administered an NRP1 inhibitor to human retinal samples treated with the SARS-CoV-2 spike protein. NRP1 has been explored by others as a promising anti-tumor target that blocks the formation of blood vessels. But so far, the applications are limited to preclinical settings.

“Mechanistically, the involvement of NRP1 in amyloid beta aggregation gives a specific molecular target for future investigation,” Hafler says. One potential application involves targeting NRP1 to prevent or treat neurological complications following COVID-19 infection.

Treating brain fog and other neurological impairments caused by viruses
The study opens up multiple avenues for future research, Hafler says. “Our study showed that exposure to SARS-CoV-2, in particular spike protein, can lead to the formation of amyloid beta aggregates in both human retinal tissue and retinal organoids.”

The study also strengthens the link between Alzheimer’s disease and microbial infection.

“It bolsters the amyloid beta antimicrobial hypothesis of Alzheimer’s disease, suggesting that amyloid beta could act as part of the brain's innate immune response against viral infections,” Hafler says. Because of its resemblance to small peptides known to bind other microbes, amyloid beta accumulation might extend to infections caused by other viruses, Hafler suspects. Further research will be needed to confirm this relationship, he adds.

Given the neurological symptoms of COVID-19, such as brain fog, Hafler and his team are investigating, in clinical studies at YSM, whether SARS-CoV-2 infection would increase the long-term risk of Alzheimer’s disease and whether this can be prevented through early treatment.

“Our ultimate goal is to prevent long-term neurological effects of COVID-19 and explore NRP1 inhibitors and other modulators of virus-host interactions as potential therapeutics for preventing viral-induced amyloid pathology and Alzheimer's disease,” Hafler says.

Source: https://medicine.yale.edu/news-article/sars-cov-2-causes-buildup-of-alzheimers-related-peptides-in-the-retina/