Johns Hopkins Medicine scientists have found new evidence that small clusters of brain tissue grown from cells from people with Alzheimer’s disease could help researchers predict how different patients may respond to medications used to control psychiatric symptoms related to the disease.
The research focused on lab-grown brain tissues called organoids. The findings add to growing evidence that these miniature brain models could eventually help scientists develop and select more precise treatments for specific groups of people with Alzheimer’s disease. Alzheimer’s is the most common form of dementia, affecting more than 7 million Americans.
The team also discovered that organoids release small particles called extracellular vesicles that carry cellular information. These particles may offer new biomarkers to diagnose Alzheimer’s disease and determine how far it has progressed.
The study, which received partial funding from the National Institutes of Health, was published in Alzheimer’s and Dementia: The Alzheimer’s Association Magazine.
Mini Brain Models Could Support Personalized Care
“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 evaluate how subgroups of patients may respond to different treatments,” says study leader Vasiliki Machairaki, Ph.D., associate professor of genetic medicine at the Johns Hopkins University School of Medicine.
There is currently no cure for Alzheimer’s disease. However, selective serotonin reuptake inhibitors (SSRIs) are often prescribed to help manage neuropsychiatric symptoms such as anxiety, depression, and agitation. These symptoms affect almost all patients, but responses to medications vary widely, Machairaki says.
Johns Hopkins researchers studied miniature models of the hindbrain, a region at the back of the skull that helps control essential functions such as breathing, sleep and heart rate. The team wanted to determine if these models could reveal molecular signatures showing whether the SSRI escitalopram oxalate could help reduce symptoms associated with Alzheimer’s disease.
Convert patients’ blood cells into brain tissue
The researchers began with blood samples collected with permission from people with Alzheimer’s disease at the NIH-funded Johns Hopkins Alzheimer’s Disease Research Center.
They reprogrammed the blood cells to return to a stem cell-like state. These cells, called induced pluripotent stem cells, can become any type of cell in the body.
Using induced pluripotent stem cells from people with Alzheimer’s disease and healthy individuals, the team created hindbrain organoids that contain specialized brain cells, or neurons, that produce the neurotransmitter serotonin.
The cells were guided to organize into small, pea-sized clumps of brain tissue that resemble the hindbrain. The study included hundreds of organoids representing individual patients with Alzheimer’s disease, as well as healthy participants. Machairaki believes it may be one of the largest brain organoid studies done so far in Alzheimer’s research.
Alzheimer’s organoids show distinct molecular changes
Organoids obtained from patients reproduced several important biological characteristics of Alzheimer’s disease at the molecular level.
Compared to organoids created from healthy individuals, those grown from cells from people with Alzheimer’s showed differences in proteins involved in communication between brain cells, inflammation and pathways associated with the disease.
The researchers then treated the organoids with escitalopram oxalate, a widely prescribed antidepressant.
In some patient-derived organoids, the drug increased proteins involved in serotonin signaling and communication between brain cells. These are pathways that antidepressants are designed to influence. Other organoids showed little or no molecular response.
“We used these organoids to model how some patients’ tissue may respond to a commonly prescribed SSRI,” says Machairaki. “On a large scale, our model could eventually be used to identify subgroups of patients, based on underlying molecular mechanisms, who are more likely to respond to certain drugs and thus help us create precise and specific long-term treatments.”
Small vesicles can reveal response to drugs
Next, the team investigated whether the extracellular vesicles released by the organoids could serve as biomarkers for Alzheimer’s disease or help researchers assess how the tissue responds to treatment.
Before and after treating the organoids with escitalopram, the scientists examined the proteins within the extracellular vesicles released by the patient-derived organoids and by healthy control organoids.
The vesicles contained proteins involved in essential brain activities, including communication between neurons, memory and the release of neurotransmitters.
Organoids grown from cells from people with Alzheimer’s showed clear changes in several proteins associated with the disease. RAB3A, NSF, and ATCAY levels were lower in Alzheimer’s organoids. These proteins play important roles in normal signaling between brain cells.
After treatment with escitalopram, the levels of some proteins increased in certain samples. The changes were especially notable in proteins connected to serotonin signaling and the synaptic pathways targeted by antidepressants.
Some organoids showed strong molecular responses, while others showed little or no changes. According to Machairaki, this variation raises the possibility that extracellular vesicles from brain organoids could eventually help identify which patients are most likely to benefit from a particular treatment.
Building more realistic brain organoids
Machairaki plans to develop more advanced organoids containing immune cells and vascular networks that mimic blood vessels. Adding these features could make the tissues more similar to living human brain tissue.
With additional research, he hopes that extracellular vesicles could one day function as a type of liquid biopsy. Such a test could help diagnose Alzheimer’s disease, determine its stage, and identify a patient’s particular disease subtype.
Machairaki emphasized that the current study represents a first step toward that goal.
In addition to Machairaki, scientists who contributed to this work include Rachel Boyd, Daiyun Dong, Ram Sagar, Waqar Ahmed,
Funding for this study was provided by the National Institutes of Health (T32 AG058527, R01AG052510, P30AG066507, 1RF1AG083801, AGR01054771, AGR01050515, AGR01046543, and AGR01071522), the Paul G. Allen Frontiers Foundation, and the Richman Center of Excellence for Precision Family Medicine in Alzheimer’s Disease at Johns Hopkins University.
No author declares a related conflict of interest according to Johns Hopkins University policies.