Stem Cell Models Reflect the Intricacies of an Alzheimer’s Brain

The Context: There are no effective treatments for Alzheimer’s disease (AD), in large part because we do not understand how patient brain cells malfunction and die. Stem cells offer an exciting opportunity to create brain cells from AD patients, allowing scientists to study how they interact and behave.

The Study: Neurons created from the stem cells of 53 deceased individuals representing the spectrum of brain aging from healthy to AD show the same hallmarks as the actual brain tissue from these individuals, finds a new study in Neuron by NYSCF scientists including Scott Noggle, PhD, and led by Tracy Young-Pearse, PhD, of Harvard Medical School and Brigham and Women’s Hospital.

Why it Matters: This study serves as a proof-of-concept that neurons created from stem cells of patients show the same features as their brain tissue, demonstrating that these cells can be used to gain insights into how the brain ages differently in different people, leading to Alzheimer’s in some but not in others. The bank of cells is now available to the wider research community as a resource for future studies.

Learn more about this study at a virtual discussion held September 22 at 5 PM ET. Register here.

This research leverages tissue samples and clinical information collected from two studies: the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP) – together called ROSMAP. ROSMAP includes thousands of participants who are tracked throughout the later stages of their life and then donate their tissues when they pass away — yielding a rich resource of clinical, cellular, and molecular data for research.

“This is a really fabulous cohort of over 3,000 people. When they enter the study, they are cognitively intact, but elderly. And then they’re followed clinically every year until death, at which time they donate all of their tissues, and we can get a very clear picture of what was happening in that person’s brain,” noted Dr. Young-Pearse.

“I thought this would be the perfect cohort to study Alzheimer’s disease because statistically, about half of the people, if they live long enough, will develop Alzheimer’s disease,” she continued. “But there are also people who are ‘super controls’: people who had perfect cognition and no pathology in their brain, so we can also look at what is different about those people.”

Stem Cells Reflect What’s Happening in an AD-Affected Brain

An especially tricky part of studying AD is that scientists can’t just reach into a patient’s brain and pull out tissue to study. But, by creating stem cells from a patient and turning these cells into the brain cells affected by AD, researchers can examine exactly how the cells affected by AD behave without an invasive biopsy or relying on mouse models, which do not fully capture how AD manifests in humans.

“Now with stem cells, we can create all different types of cells in the brain from these participants and study the biology of the disease process,” said Dr. Young-Pearse. “We can try to understand what genetic drivers are increasing risk for Alzheimer’s disease, and which genes may be influencing cognitive resilience.”

“For this study, we were interested in showing that neurons created from the stem cells of ROS/MAP participants reflect the cellular features of the tissue samples collected in ROSMAP,” said Dr. Noggle. “Doing this really solidifies that these stem cells are a robust and reliable model for studying neurodegenerative disease processes.”

The team examined a variety of cellular features including presence of plaques and tangles (the central hallmarks of AD), and found that the stem-cell-derived neurons did in fact reflect the characteristics present in brain tissue. 

Additionally, no two AD patients are the same, and understanding what makes each patient unique will be especially important for accelerating personalized medicine. The researchers found that the AD features represented in the stem-cell-derived neurons reflected the diversity of the characteristics found in the patient cells themselves – an exciting result. 

“Knowing that these stem-cell-derived neurons capture individualized, disease-relevant biology is an important step toward discovering exactly how AD progresses in brian cells and how we can prevent or reverse it,” remarked Dr. Noggle.

Moving Toward Better Treatments

While much of AD research has traditionally been centered on plaques made of the amyloid protein, we need to take a more comprehensive approach to find better treatments. 

“Drugs that clear these plaques don’t always fare well in clinical trials, suggesting that there’s more at play than we currently understand,” noted Dr. Noggle. “To find better treatments, we need to look beyond plaques, and these stem cells allow us to do that all while studying how individual genetics may further influence the disease process.”

Perhaps most importantly, the stem cells created in this study are now available as a resource to accelerate AD research around the world.

“We are excited to continue our work with these cells and to share them throughout the community to enable better understanding and treatment of Alzheimer’s,” said Dr. Noggle.

Journal article:

Stem cell-derived neurons reflect features of protein networks, neuropathology, and cognitive outcome of their aged human donors
Valentina N. Lagomarsino, Richard V. Pearse II, Lei Liu, Yi-Chen Hsieh, Marty A. Fernandez, Elizabeth A. Vinton, Daniel Paull, Daniel Felsky, Shinya Tasaki, Chris Gaiteri, Badri Vardarajan, Hyo Lee, Christina R. Muratore, Courtney R. Benoit, Vicky Chou, Seeley B. Fancher, Amy He, Julie P. Merchant, Duc M. Duong, Hector Martinez, Monica Zhou, Fatmata Bah, Maria A. Vicent, Jonathan M.S. Stricker, Jishu Xu, Eric B. Dammer, Allan I. Levey, Lori B. Chibnik, Vilas Menon, Nicholas T. Seyfried, Philip L. De Jager, Scott Noggle, Dennis J. Selkoe, David A. Bennett, Tracy L. Young-Pearse. Neuron. 2021. DOI: https://doi.org/10.1016/j.neuron.2021.08.003

Illustration credit: Kiran Pearse