Researchers at the Johns Hopkins School of Medicine have unveiled groundbreaking evidence suggesting that small clusters of brain tissue, known as organoids, derived from Alzheimer’s disease patients may assist scientists in predicting patient responses to medications aimed at managing psychiatric symptoms linked to Alzheimer’s disease.
This innovative study highlights the potential of lab-grown brain tissue to pave the way for more targeted treatments for distinct subsets of Alzheimer’s patients. Alzheimer’s disease, recognized as the most prevalent form of dementia, currently impacts over 7 million Americans.
In their findings, the researchers identified that these organoids secrete tiny particles called extracellular vesicles, which contain critical cellular information. These vesicles could emerge as new biomarkers for diagnosing Alzheimer’s disease and tracking its progression.
This pivotal research received partial funding from the National Institutes of Health and was published in the Alzheimer’s Disease and Dementia: Journal of the Alzheimer’s Association.
Mini-brain models pave the way for personalized care
“Our research indicates that large-scale patient-derived brain organoids and their secreted vesicles may be effective in staging Alzheimer’s disease, exploring its underlying mechanisms, and evaluating how different patient subgroups respond to various treatments,” stated study leader Dr. Vassiliki Machairaki, an associate professor of medical genetics at the Johns Hopkins University School of Medicine.
As of now, no cure exists for Alzheimer’s disease. Nevertheless, selective serotonin reuptake inhibitors (SSRIs) are frequently administered to mitigate neuropsychiatric symptoms such as anxiety, depression, and agitation. Despite these symptoms being common in Alzheimer’s patients, individual responses to medications can vary significantly, according to Dr. Machairaki.
Researchers at Johns Hopkins have been examining miniature models of the hindbrain, a crucial brain area responsible for regulating key functions including breathing, sleep, and heart rate. The team aimed to find out whether these models could reveal molecular indicators that predict the effectiveness of the SSRI escitalopram oxalate in alleviating symptoms associated with Alzheimer’s disease.
Transforming blood cells into brain tissue
The researchers initiated their work with blood samples collected, with consent, from Alzheimer’s patients through the NIH-funded Johns Hopkins Alzheimer’s Disease Research Center.
They then reprogrammed these blood cells back to a stem cell-like state. Known as induced pluripotent stem cells, these versatile cells can differentiate into any cell type within the body.
Using induced pluripotent stem cells extracted from both Alzheimer’s patients and healthy individuals, the team produced hindbrain organoids featuring specialized brain cells, or neurons, that synthesize the neurotransmitter serotonin.
The cells were encouraged to form small pea-sized clusters of brain tissue that mimicked the hindbrain. This study encompasses hundreds of organoids representing both Alzheimer’s patients and healthy controls. Dr. Machairaki believes this could be among the largest brain organoid studies conducted in the realm of Alzheimer’s disease research.
Alzheimer’s disease organoids exhibit distinct molecular changes
These patient-derived organoids reflected multiple critical biological attributes of Alzheimer’s disease at the molecular level.
Compared to organoids created from healthy individuals, those generated from Alzheimer’s patients exhibited variances in proteins crucial for communication between brain cells, inflammation, and pathways relevant to Alzheimer’s disease.
The researchers treated the organoids with escitalopram oxalate, a commonly prescribed antidepressant.
In certain patient-derived organoids, the drug enhanced the levels of proteins that engage in serotonin signaling and facilitate communication between brain cells—pathways that antidepressants aim to target. Conversely, other organoids displayed negligible molecular response.
“We utilized these organoids to model the response of tissues from various patients to frequently prescribed SSRIs,” Dr. Machairaki explained. “On a broader scale, our model could help identify patient subgroups more likely to respond positively to specific drugs based on their unique molecular mechanisms, potentially leading to the development of targeted therapies.”
Tiny vesicles could reveal drug reactions
The research team further explored whether the extracellular vesicles released from organoids could serve as valuable biomarkers for Alzheimer’s disease or assist in evaluating tissue responses to treatments.
They examined proteins in extracellular vesicles emitted from both patient-derived and healthy control organoids, before and after escitalopram treatment.
The vesicles encompassed proteins vital for crucial brain functions, such as neuron communication, memory, and neurotransmitter release.
Organoids derived from Alzheimer’s patients showcased notable alterations in several disease-associated proteins. Levels of RAB3A, NSF, and ATCAY were diminished in Alzheimer’s disease organoids, indicating their roles in normative signaling between brain cells.
After escitalopram treatment, certain proteins increased within specific samples, particularly those involved in serotonin signaling and synaptic pathways targeted by antidepressants. Some organoids exhibited strong molecular responses while others showed minimal changes, hinting at the potential for extracellular vesicles in brain organoids to identify patients who would benefit from specific treatments.
Advancing brain organoid technology
Professor Machairaki aims to advance the development of more complex organoids incorporating immune cells and networks resembling blood vessels, enhancing their similarity to living human brain tissue.
With further exploration, she envisions extracellular vesicles functioning as a form of liquid biopsy, facilitating the diagnosis of Alzheimer’s disease, gauging its severity, and pinpointing a patient’s specific disease subtype.
Professor Machairaki notes that this study is merely a foundational step towards that goal.
In addition to Machairaki, the study included contributions from Rachel Boyd, Daiyun Dong, Ram Sagar, Waqar Ahmed, Zenia Androni, Paul Rosenberg, Konstantin Riquesos, and Kenneth Witwer from Johns Hopkins University, Anton Ilyuk from Timora Analytical Operations, and Anton Polsteinsson from the University of Rochester School of Medicine and Dentistry.
This research was supported by the National Institutes of Health (T32 AG058527, R01AG052510, P30AG066507, 1RF1AG083801, AGR01054771, AGR01050515, AGR01046543, AGR01071522), the Paul G. Allen Frontiers Foundation, and the Richman Family Precision Medicine Center of Excellence Alzheimer’s Disease Research Center at Johns Hopkins University.
In line with Johns Hopkins University policy, none of the authors report any relevant conflicts of interest.
Source: www.sciencedaily.com