Stem Cell-Derived Neurons Mimic Alzheimer’s Pathogenesis

(Posted on Monday, November 22, 2021)

This story is part 6 of an occasional series on the current progression in Regenerative Medicine. In 1999, I defined regenerative medicine as the collection of interventions that restore to normal function tissues and organs that have been damaged by disease, injured by trauma, or worn by time. I include a full spectrum of chemical, gene, and protein-based medicines, cell-based therapies, and biomechanical interventions that achieve that goal.

A recent paper displays striking progress in Alzheimer’s disease research. A team from Brigham and Women’s Hospital and Harvard Medical School has discovered methods to grow neurons and brain tissue from stem cells that surprisingly, imitate the unique characteristics of donors with Alzheimer’s.

Alzheimer’s is a disease that affects approximately 50 million people worldwide. It is characterized by gradual cognitive decline and is often undetected until late stages of the disease. This has prevented researchers from understanding its root causes as studies are typically limited to just those with advanced cases.

Lagomarsino et al. has discovered that tissues grown from stem cells imitate the distinct characteristics of Alzheimer’s that are found in an individual’s brain. This is a significant study that could provide a new window of research into the molecular causes of Alzheimer’s disease and allow scientists to study how Alzheimer’s progresses differently across individuals.

The study began with some help from two ongoing projects: The Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP). Both ROS and MAP collect data on the cognitive abilities of volunteers over the course of several years. In combination, the two studies have collected a full spectrum of data on the rate of Alzheimer’s disease progression in different individuals.

ROS/MAP researchers also stain brain samples to study the physical characteristics of deceased participant brains. Specifically, they look for the abundance of two abnormally folded proteins called amyloid plaques and tau tangles. The current leading theory about the root causes of Alzheimer’s disease is that the expression of these abnormal proteins is what induces cognitive decline in patients.

Lagomarsino et al. specifically chose to study subjects from the ROS/MAP database that spanned the entirety of the Alzheimer’s severity spectrum. Overall, the researchers chose to use data from 53 deceased ROS/MAP participants, 16 of whom had been formally diagnosed with Alzheimer’s.

Researchers then collected cryopreserved pluripotent blood stem cells from each subject. Pluripotent stem cells have the ability to replicate themselves or produce any other cell/tissue in the body. The researchers used these versatile cells to regrow brain cells and tissues from each subject.

Lagomarsino et al. discovered that the stem cell-derived tissues displayed unique characteristics of the participant’s original brains. The stem-cell grown tissues exhibited 110 genes that matched each individual’s original brain tissue. In addition, the lab-grown tissues displayed elevated levels of proteins such as amyloid-beta-40 and amyloid-beta-42 that were strongly correlated with the existence of plaques and tangles in the original brain.

If these results are reproducible and validated, this study is truly remarkable. The idea that we can take simple cells from an individual and grow them into tissue that imitates the brain of someone with Alzheimer’s suggests that Alzheimer’s is not a disease that begins just in the brain or with age but is caused by intrinsic properties of a person’s cells. This may be due to genetics, it may be due to genomic imprinting which occurs during embryonic development, or it may be influenced by some environmental factors. Another implication of this study is that there could be methods to predict the onset of Alzheimer’s from a very early age just by studying a person’s genome or by growing brain tissue from their cells.

This study has real potential to shift our entire understanding of the root causes and molecular basis of Alzheimer’s. As further research is conducted with this technique, we may finally see some progress in unraveling the mysteries of Alzheimer’s disease and perhaps begin to form an understanding of how to identify, prevent, and treat the disease altogether.

Read the full article on Forbes.