Study Uses Lab-Grown Brain Tissue to Explore Alzheimer's and Drug Response
Scientists from Johns Hopkins Medicine have conducted a new study using lab-grown brain tissues, called organoids, derived from patients with Alzheimer's disease and healthy individuals. The research, published on April 8 in Alzheimer's & Dementia: The Journal of the Alzheimer's Association, focused on hindbrain organoids, which model the brain's command center for regulating functions like breathing and heart rate.
"Our study suggests that large-scale, patient-derived brain organoids and the vesicles they secrete can help us stage Alzheimer's disease, investigate the mechanisms that drive it and assess how patient subgroups may respond to different treatments," said study leader Vasiliki Machairaki.
The work was funded by the National Institutes of Health, the Paul G. Allen Frontiers Foundation, and the Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease at Johns Hopkins University.
How the Study Was Conducted
Researchers collected blood samples from patients at the Johns Hopkins Alzheimer's Disease Research Center. With permission, they reprogrammed the blood cells into induced pluripotent stem cells, which can develop into any cell type. These stem cells were then used to create hundreds of hindbrain organoids containing serotonin-secreting neurons, representing both Alzheimer's patients and healthy controls.
The team exposed the organoids to escitalopram oxalate, a commonly prescribed antidepressant (SSRI), to observe their response.
Key Findings
The patient-derived organoids showed distinct molecular-level changes compared to healthy controls. These included alterations in proteins involved in brain cell communication, inflammation, and disease pathways.
When treated with the antidepressant, the response varied significantly. Some organoids showed increased levels of proteins involved in serotonin signaling and brain cell communication. Others showed little to no response to the drug.
Extracellular vesicles—tiny particles secreted by the organoids—from Alzheimer's patient-derived samples showed distinct protein changes. These included reduced levels of RAB3A, NSF, and ATCAY proteins, which are important for normal brain signaling. After antidepressant treatment, some of these protein levels increased in certain samples.
Implications and Future Directions
Machairaki noted that existing therapies like SSRIs vary widely in their effectiveness for treating neuropsychiatric symptoms in Alzheimer's patients.
"We used these organoids to model how some patients' tissue may respond to a commonly prescribed SSRI. On a large-scale level, our model may eventually be used to identify subgroups of patients, based on underlying molecular mechanisms, who are more likely to respond to certain drugs."
Looking ahead, Machairaki aims to engineer more advanced brain organoids that incorporate immune cells and vascular-like networks to better simulate living brain tissue. The researchers also envision using extracellular vesicles as a potential liquid biopsy tool for diagnosing and staging Alzheimer's disease subtypes.
This study represents preliminary steps toward more precise, targeted treatments for Alzheimer's disease.
Contributors
Scientists from Johns Hopkins included Rachel Boyd, Daiyun Dong, Ram Sagar, Waqar Ahmed, Xenia Androni, Paul Rosenberg, Constantine Lyketsos, and Kenneth Witwer. Additional contributors were Anton Iliuk from Tymora Analytical Operations and Anton Porsteinsson from University of Rochester School of Medicine and Dentistry.