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Researchers use brain organoids to understand the variable and complex nature of Alzheimer’s disease.

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Patient cells and serum create better Alzheimer’s disease models

Many potential treatments for Alzheimer’s disease have been found using mouse models, but they often don’t translate well to humans. Will organoids provide the answers that neuroscientists need to develop new treatments?
Natalya Ortolano, PhD Headshot
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Mice have no reason to fear diseases that keep humans up at night. Researchers have developed effective treatments in mice against diseases that plague mere mortals such as Alzheimer’s disease and cancer, but these treatments often fail once they exit the mouse house and enter the hospital. Humans share 92% of our genome sequences with mice, but the seemingly minimal 8% makes all the difference. That’s why researchers turn to sci-fi-like human models to identify new drug targets and screen their effects: organoids.

The most common form of dementia, Alzheimer’s disease, is particularly tricky to model in a mouse. Although mouse models of the neurodegenerative disease exist, the mutation they carry links to only 5% of all cases. The other 95% of cases are considered “sporadic” and likely occur due to a combination of known genetic risk factors, lifestyle, and environment. But mice don’t spontaneously develop Alzheimer’s disease as they age like humans do, making them a weak model for this complex disease.

Researchers can study this disease with fresh eyes thanks to brain organoids, clumps of neuronal cells differentiated from human pluripotent stem cells that self-organize to form the intricate layers of the brain. Neuroscientists rely on several strategies to craft the perfect human model for Alzheimer’s disease drug discovery, including using patient cells.

“I hope that organoids will help us to discover something we haven’t seen in current animal models,” said Shuibing Chen, a stem cell researcher at Weill Cornell Medicine. “People who work on stem cells and even some people who work on animal models appreciate the limitations of animal models. The whole field is welcoming new models for drug testing and disease modeling. The most important thing is that we want to make sure that we continually improve the current organoid model to make it closer and closer to what happens in vivo.”

From the head to the dish

Jong-Chan Park, a neuroscientist from Seoul National University, used brain organoids derived from the cells of eleven patients with sporadic Alzheimer’s disease to model the disease and screen FDA-approved drugs that eradicate key pathologies (1).

The hallmark of Alzheimer’s disease is tangled aggregates of proteins inside dying neurons surrounded by plaques composed of protein fragments. These dying neurons trigger an immune response that causes brain inflammation, another symptom of the disease. People with Alzheimer’s disease experience severe neurological symptoms that worsen as the disease progresses, including memory loss, confusion, and problems reading and writing.

Park wanted to recapitulate these pathological features in organoids. He and his colleagues reprogrammed blood cells from patients with sporadic Alzheimer’s disease who were and were not at high risk of developing tangles and plaques into induced pluripotent stem cells, which can differentiate into virtually any cell in the body. They differentiated these cells into neurons and clustered them to form a whopping 1,300 organoids, which they grew for 60 days.

The team did extensive RNA sequencing on the patient-derived brain organoids and found more than 1,000 differentially expressed genes compared to samples derived from people without Alzheimer’s disease. Most of the differentially expressed genes related to Alzheimer’s disease pathology.

A colorful MRI image of the brain is shown.
MRI images and PET scans of the brain help clinicians diagnose Alzheimer’s disease.
Credit: istock/Highwaystarz-Photography

They also found that cells from patients at higher risk for developing tangles and plaques had more plaques than patients not at risk. The number of plaques correlated to that observed in the corresponding patient’s brain, which was measured by Pittsburgh compound B (PiB)-positron emission tomography (PET) prior to tissue collection.

“The most exciting part was really the organoids,” said Park. “The organoids really were uniform in size, and they were homogeneous in their composition. And this enabled us to perform drug screening using a high content screening system.”

Park and his collaborators used mathematical modeling to analyze the disrupted pathways and identify druggable targets. They then screened FDA-approved drugs that targeted these pathways and measured their efficacy by assessing cell death and the accumulation of plaques and tangles. This resulted in an extensive list of potential drugs to follow-up on, as well as a drug screening platform that can be applied to studying other neurological diseases.

The protocol isn’t easy to implement, but Park provided extensive detail in his paper so that others could replicate it. He and his team continue to finetune the system, while encouraging others to consider the limitations of the organoid system before using it to screen new drugs. 

Most importantly, the organoids he developed did not have many glial cells — the brain's non-neuronal cellular support system — which are present in a fully developed brain. He recommends that researchers continue growing the organoids for 100 or 200 days, a test that he's currently working on himself.

Just add serum

The lack of glial cells in Park’s mini brains begs an important question: can brain organoids really model neurodegenerative diseases? Brain organoids have the cellular make-up and gene expression pattern of an early fetal brain, not the brain of an 80-year-old, the age at which half of patients are commonly diagnosed.

“We spent several years trying to model Alzheimer's disease using brain organoids. We introduced the different genetic risk factors, but we were not able to see a phenotype. And then we realized that maybe because human-derived induced pluripotent stem cells are phenotypically young, it may be intrinsically difficult to model an associated degenerative disease. So, then we thought, ‘how can we use the organoids in a creative manner?’” said Yanhong Shi, a stem cell biologist at the Beckman Research Institute of City of Hope.

Shi thought about the blood brain barrier since patients with Alzheimer’s disease often have a leaky blood brain barrier. Rather than develop a vascular system for her brain organoids, she decided to expose them to human serum to mimic the leaking fluid the brain would see if the blood brain barrier wasn’t as selective as it should be (2).

Like Park’s team, Shi saw increased numbers of plaques, tangles, and malfunctioning neurons. Gene expression analysis confirmed neuronal dysfunction and hinted at a heightened immune response similar to that observed in the inflamed brains of people with Alzheimer’s disease.

Whether using a patient-derived cell model of the human brain or a serum-stressed brain, researchers are excited about the potential applications of brain organoids for drug screening and discovery.

“My ultimate goal is to be able to develop a drug. We first try to understand the pathophysiology using organoids, but that's not the end of it. That's only the start,” said Shi.

References

  1. Park, J-C. et al. A logical network-based drug-screening platform for Alzheimer’s disease representing pathological features of human brain organoids. Nat Comms  12, 280 (2021).
  2. Chen, X. et al. Modeling Sporadic Alzheimer's Disease in Human Brain Organoids under Serum Exposure. Adv Sci  8, 18 (2021).

About the Author

  • Natalya Ortolano, PhD Headshot

    Natalya received her PhD in from Vanderbilt University in 2021; she joined the DDN team the same week she defended her thesis. Her work has been featured at STAT News, Vanderbilt Magazine, and Scientific American. As an assistant editor, she writes and edits online and print stories on topics ranging from cows to psychedelics. Outside of work you can probably find her at a concert in her hometown Nashville, TN.

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July/August 2022 : Volume 18 : Issue 7
Volume 18 - Issue 7 | July/August 2022

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