How Brain Organoids Can Help Us Understand Neurodegenerative Disorders

By: Kate Leinenweber

Image: Dish of brain organoids sitting on a microscope

I hold a memory in the back of my mind that reminds me of why I research what I do: my grandmother, lying prone on her hospice bed, her skin pale, her bones nearly visible beneath her skin. Her breathing continues, although I have to strain to hear it, before finally slowing down and stopping. At that point, she was long incapacitated by debilitating memory loss, and she could no longer speak or feed herself. She had been bedridden for 19 months after she forgot how to walk. I remember wondering what her brain might have looked like after degrading for that long. I know what took her life away from her, just as it has for six and a half million people across the United States. 

The Struggle for Finding an Alzheimer’s Cure

Nearly everyone has a story of a relative or loved one who suffered (or suffers) from Alzheimer’s disease; it’s not uncommon, yet over a century after the disease’s discovery, there are very few treatments that can help manage symptoms of the disease, let alone halt its prognosis. This is not just an issue when it comes to Alzheimer’s disease. Countless other neurodegenerative disorders suffer from the same prognosis: Parkinson’s disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy, Lewy body dementia, and more. Diagnosis is a question of how many years someone has left, not whether they’ve caught the disease early enough to cure it. And the family members of people with such disorders are forever plagued with the worry: what if this happens to me, too? 

  Many neurological diseases lack treatments and possible cures because of a lack of understanding (Jalink & Caiazzo, 2021). They do not progress like pathological diseases, and they do not tend to originate from a single gene mutation– this makes them hard to track genetically, and it means that there is no obvious target for potential drugs. In addition to this, brain research is difficult to conduct. Human brain samples can only be collected after a patient is deceased, not to mention that they must have previously elected to donate their brains to science, an option which many patients and families do not consider or even want to think about‡. Although mouse models are an effective way of modeling brain disease, they don’t always mirror human systems as well as needed, and there are many ethical considerations to be made when choosing to work with mice. Scientists have even developed single-layer cultures of specific cell types like neurons, which can help us look at very specific interactions between diseased cells. However, they only provide one dimension of clarity, and drugs tested in these models don’t always translate effectively to actual patients (Gerakis & Hentz, 2019).

Many of the models we use in scientific research are effective, but not ideal, so continuing to improve older models and develop new ones is important to cover all of our bases. This is where a more recent research development comes into play: brain organoids. 

What are Brain Organoids?

Image: Brain organoids viewed under a microscope, 4x magnification.

Brain organoids, lovingly coined ‘mini-brains’, are spherical models of brain tissue that can be used to model the brain’s structure and function. They are produced by culturing stem cells in a way that coaxes them to differentiate into the various cells of the brain, including neurons and glia. The early growth stages of organoids mimic human brain development, so brain organoids have widely been used to model disorders that arise during development, such as autism and psychiatric disorders like schizophrenia and depression (Jalink & Caiazzo, 2021). They have also been used to model neurodegenerative diseases like Alzheimer’s and Parkinson’s by allowing the organoids to mature for longer and represent later stages of brain development.

Brain organoids are extremely useful for researching disorders of the brain for various reasons. For one, they are 3D models with multiple cell types representative of the entire brain, which can provide more complex architecture than single-layer cultures (Corrò, et. al., 2020). They also provide a way to compare genetic variations in a controlled environment and resemble human disease pathology more accurately than animal models. Finally, they make it possible to research disease stages that are hard to obtain samples for, such as the early stages of neurodegeneration.

Modeling Neurodegeneration in Organoids

There are multiple ways that neurodegenerative disease can be modeled in organoids. For example, skin tissue samples from patients with disorders such as Alzheimer’s can be induced to become stem cells, and then used to create organoids displaying Alzheimer’s pathology (Gonzalez, et. al., 2018). Models like these can be used to study the course of the disease and the interactions that cause it on a molecular level, such as why amyloid plaques (a hallmark of Alzheimer’s) start to accumulate in the brain or how the immune system responds to disease onset. 

Another way that many labs generate brain organoids is by using stem cells that have been gene edited to have Alzheimer’s-associated mutations.  With this method, it is possible to research how much specific gene mutations affect the onset of Alzheimer’s, which can help with genetic testing for the disease in the future. This type of genetic testing is already available for a gene called APOE, which is heavily connected to Alzheimer’s risk (Raulin, et. al., 2022). With the help of modeling technologies like organoids, efforts are already in progress to model how other gene mutations can contribute to the disease.

Future Hopes: Why this Matters

As research techniques continue to improve, scientists will be able to discover the mechanisms behind why Alzheimer’s occurs and what exactly happens in the body during disease onset. It’s extremely important with this in mind to support new technologies like organoid research and gene editing, which can often be met with skepticism due to their novelty and their media presentation as something out of science fiction, when in reality they are just a more complex type of cell culture. However, they should not be treated as the ‘best’ research model either– each type of research model has its own benefits, and the combination of multiple models and efforts (including brain donations, mouse models, and single-layer cultures) is necessary for finding disease treatments. 

Together, these technologies have been invaluable in helping scientists discover more about neurological disease than was ever thought possible, including the genetic basis behind different diseases and drug testing for new treatments. In the future, recent leaps and bounds in Alzheimer’s research can help us create better and more precise disease treatments that don’t just buy patients time, but allow them to keep living high quality lives after diagnosis.

Footnote

‡ I regret that I never asked my family to register my grandma as a brain donor. For all the pain that she and our family went through because of Alzheimer’s disease, her brain could have been used to further research a cure.

If you or someone you love is interested in registering as a brain donor (which anyone over 18 can do), you can visit the NIH and Alzheimer’s Association sites below for more info:

NIH: https://www.nia.nih.gov/health/brain-donation/brain-donation-gift-future-generations

Alzheimer’s Assoc.: https://www.alz.org/alzheimers-dementia/research_progress/brain-donation

Sources:

Corrò, C., Novellasdemunt, L., Li, V.S.W. (2020).  A brief history of organoids. American Journal of Physiology - Cell Physiology 319(1), C151-C165. https://doi.org/10.1152/ajpcell.00120.2020.

Gerakis, Y., Hetz, C. (2019).Brain organoids: a next step for humanized Alzheimer’s disease models?. Mol Psychiatry 24, 474–478. https://doi.org/10.1038/s41380-018-0343-7.

Gonzalez, C., Armijo, E., Bravo-Alegria, J. et al. (2018). Modeling amyloid beta and tau pathology in human cerebral organoids. Mol Psychiatry 23, 2363–2374. https://doi.org/10.1038/s41380-018-0229-8.

Gustavsson, A., Norton, N., et. al. (2022). Global estimates on the number of persons across the Alzheimer's disease continuum. Alzheimer’s and Dementia, 19(2), 650-670. https://doi.org/10.1002/alz.12694.

Jalink, P., & Caiazzo, M. (2021). Brain Organoids: Filling the Need for a Human Model of Neurological Disorder. Biology, 10(8), 740. https://doi.org/10.3390/biology10080740.

Raulin, AC., Doss, S.V., Trottier, Z.A. et al. (2022). ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies. Mol Neurodegeneration 17, 72. https://doi.org/10.1186/s13024-022-00574-4.