Brain organoids may guide Alzheimer’s diagnosis and treatment

Scientists from Johns Hopkins Medicine report new evidence that clusters of brain tissue derived from the cells of patients with Alzheimer's disease may be used to evaluate how certain patients with the neurodegenerative condition may respond to drugs commonly prescribed to treat psychiatric symptoms of the disorder. 

The findings, based on a study of lab-grown brain tissues known as organoids, contribute to a growing body of evidence that brain organoids may also one day be used to more precisely develop and prescribe treatments for subgroups of patients with Alzheimer's disease, which is the most common form of dementia, and affects more than 7 million Americans.

In addition, the researchers found that tiny particles, known as extracellular vesicles, which are secreted by organoids, may contain cellular information that could help scientists find new biomarkers to diagnose and stage Alzheimer's disease.

A report of the findings, funded in part by the National Institutes of Health, was published April 8 in Alzheimer's & Dementia: The Journal of the Alzheimer's Association. 

"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," says study leader Vasiliki Machairaki, Ph.D., associate professor of genetic medicine at the Johns Hopkins University School of Medicine.

While there are no cures for Alzheimer's disease, existing therapies, such as selective serotonin reuptake inhibitors (SSRIs), are commonly prescribed for patients with neuropsychiatric symptoms, including anxiety, depression and agitation, but vary widely in their ability to treat the symptoms that nearly all patients experience, Machairaki says.

The Johns Hopkins team set out to analyze mini models of the hindbrain, the brain's command center in the back of the skull that regulates vital functions including breathing, sleep and heart rate. Such models may reveal molecular signatures of whether an SSRI drug, escitalopram oxalate, is effective in curbing Alzheimer's disease symptoms.

From blood samples collected with permission from patients with Alzheimer's disease at the NIH-funded Johns Hopkins Alzheimer's Disease Research Center, the scientists coaxed blood cells to turn back their internal clocks to become induced pluripotent stem cells, which can turn into any cell type within the body.

The researchers then generated hindbrain organoids containing specialized brain cells, or neurons, that secrete the neurotransmitter serotonin from induced pluripotent stem cells derived from patients with Alzheimer's disease and healthy individuals. The scientists differentiated these cells into self-organizing, small, pea-sized clusters of brain tissue that resemble the hindbrain. With hundreds of hindbrain organoids representing individual patients with Alzheimer's disease and healthy individuals, Machairaki believes this may be one of the largest studies of brain organoids to date to study the disease.

Using patient-derived brain organoids, the researchers found that these lab-grown tissues reflect important biological features of Alzheimer's disease at the molecular level. Compared to organoids from healthy individuals, those derived from patients with Alzheimer's showed changes in proteins involved in brain cell communication, inflammation and disease-related pathways.

The team then exposed the organoids to escitalopram oxalate, a commonly prescribed antidepressant. In some patient-derived organoids, the drug increased levels of proteins involved in serotonin signaling and communication between brain cells, pathways known to be targeted by antidepressants. In other organoids, the scientists observed little to no changes. "We used these organoids to model how some patients' tissue may respond to a commonly prescribed SSRI," Machairaki says. "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 and thus help us to create precise, targeted treatments in the long run."

Next, the researchers examined whether tiny particles released by the organoids, extracellular vesicles, could serve as biomarkers for the disease and help evaluate drug response.

Before and after treatment with the antidepressant escitalopram, the team analyzed the protein content of extracellular vesicles released from patient-derived organoids, as well as from healthy controls. These extracellular vesicles carried proteins involved in key brain functions such as communication between neurons, memory and neurotransmitter release.

Organoids derived from patients with Alzheimer's showed distinct changes in several proteins linked to the disease, including reduced levels of proteins such as RAB3A, NSF and ATCAY, which are important for normal brain cell signaling. After treatment, some of these proteins increased in certain samples, particularly those involved in serotonin signaling and synaptic pathways targeted by antidepressants.

The scientists observed strong molecular changes in some organoids, and little to no response in others. This variability suggests that extracellular vesicles from brain organoids could potentially be used to identify which patients are more likely to benefit from specific treatments, Machairaki says.

Next, Machairaki aims to engineer advanced brain organoids that incorporate immune cells and vascular-like networks capable of simulating blood vessels, in efforts to improve the tissues' similarity to living brain tissue.

With further research, Machairaki envisions using extracellular vesicles as a kind of liquid biopsy to diagnose and stage a patient with a distinct subtype of Alzheimer's disease. She notes that this study represents preliminary steps in that direction. 

In addition to Machairaki, scientists who contributed to this work include Rachel Boyd, Daiyun Dong, Ram Sagar, Waqar Ahmed, Xenia Androni, Paul Rosenberg, Constantine Lyketsos and Kenneth Witwer from Johns Hopkins, Anton Iliuk from Tymora Analytical Operations and Anton Porsteinsson from University of Rochester School of Medicine and Dentistry.

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 Family Precision Medicine Center of Excellence in Alzheimer's Disease at The Johns Hopkins University.