| FEATURES & INNOVATIONS |
is using stem cells derived from patients with neurodegenerative diseases to develop 3D models of the brain. “Mini brains offer better models of aging diseases because they can mimic what is happening in a 60 year old’s brain, unlike the fetal neurons represented by 2D cultures,” says Shi-Yan, who is looking for a very specific change which kills neural cells in the diseased brain. Sick neurons do not die without a sign.
Their demise is precipitated by a gradual toxic accumulation of proteins: clusters of alpha-synuclein in Parkinson’s, clumps of amyloid-beta in Alzheimer’s, and a combination of many different proteins in amyotrophic lateral sclerosis (ALS). Researchers believe that these lethal clusters
can spread like an infectious plague between neurons, and even to supportive glial cells. Shi-Yan’s models could help to explain if and how these toxins seep through brain tissue. The results could have implications for surgery because sterilizing instruments does not eliminate the proteins. Depending on how the proteins are found to aggregate, surgeons may be guided to destroy their instruments after operating on patients with Parkinson’s disease. These are early days for Shi-Yan, but so
far, she has been able to create spherical brain organoids of Parkinson’s disease, in which the neurons die at a faster rate than in healthy organoids. More intriguing, however, is that the diseased cells accumulate alpha-synuclein proteins in dense clusters — something that has never been seen before in a cell model. The methods developed by Shi-Yan could
also be used to predict whether a healthy young adult test subject will develop Parkinson’s disease in 50 years. Researchers could take samples of their cells, age them by a few decades, and watch for any pathogenic effects. “We’d be able to see neurons dying within a month, which is really quick,” she says.
Day 0
One of the tiny midbrains produced by Huck Hui Ng’s team.
In the blood vessels Researchers could detect neurodegeneration even earlier if they looked beyond the nervous system. Christine Cheung at the IMCB has taken a hint from the famous words of 17th century English physician, Thomas Sydenham: “A man is as old as his arteries.” “Blood vessels are like silent killers,”
says Christine. This is especially apparent in a form of cognitive decline caused by blocking the brain of its blood supply, such as during a stroke. “In vascular dementia, blood vessel damage occurs before the neurons begin to die,” says Christine. “With the current focus on preventative medicine, there is cause for looking at early events.” Christine is growing stem cell models of blood vessels to better understand how one system affects the other. Not all blood vessels are the same,
however. Unlike blood vessels to the other organs, those to the brain have to meet a higher demand for nourishment to feed our thoughts, memories and coordinated move- ments. The vessels are structurally distinct,
Day 7
and are believed to play a role in draining the brain of the toxic amyloid-beta proteins found in Alzheimer’s patients. But these functions are not visible using standard models of blood vessels. In 2014, Christine grew the first brain-spe- cific line of blood vessels2
. She derived them
from a specific type of embryonic tissue known as the neural crest, made with stem cells. The blood vessel cells clearly showed that the brain’s vasculature is essential for clearing out excess amyloid-beta proteins. Ves- sels exposed to low-oxygen conditions, typical in a stroke, could not pump the proteins out as efficiently. “Without organ-specific blood vessel cells to model disease processes, it is hard to have an accurate picture of what could have gone wrong.” Christine sees huge potential for intro-
ducing her vascular cells to the 3D organoids developed by Huck Hui and Shi-Yan for tissue engineering applications. “We are all taking small steps toward the
long-term goal of coming up with more effec- tive drugs for neurodegenerative diseases,” says Shi-Yan. “In a few years, someone will piece all these disparate studies together like a jigsaw puzzle and finally solve it.”
1. Jo, J., Xiao, Y., Sun, A. X., Cukuroglu, E., Tran, H.-D. et al. Midbrain-like organoids from human pluripotent stem cells contain functional dopaminergic and neuromelanin-producing neurons. Cell Stem Cell 19, 248–257 (2016).
Blood vessel cells are capable of clearing amyloid-beta proteins (red), which are transported to organelles (blue) for enzymatic degradation.
34 A*STAR RESEARCH
2. Cheung, C., Goh, Y. T., Zhang, J., Wu, C. & Guccione, E. Modeling cerebrovascular pathophysiology in amyloid-β metabolism using neural-crest-derived smooth muscle cells. Cell Reports 9, 391–401 (2014).
ISSUE 6 | JANUARY – MARCH 2017
Reproduced from Ref. 2 and licensed under CC BY 3.0 (
https://creativecommons.org/licenses/by/3.0/) © 2014 C. Cheung et al.
© 2017 A*STAR Genome Institute of Singapore
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