Kristin Freude’s Neurodegenerative Disease Lab

Applications of CRISPR Gene Editing to Study Alzheimer’s Disease

by Tenzin Dothar

Background

The term dementia refers to a set of symptoms associated with a decline in memory function and other cognitive skills to the point where it interrupts an individual’s ability to complete daily tasks. The most common type of dementia is Alzheimer’s disease (AD), a neurodegenerative disease that can present in one of two forms: familial Alzheimer’s disease (fAD) or sporadic Alzheimer’s disease (sAD) (Tcw & Goate, 2017). In the US, more than five million Americans are living with AD, with this number projected to increase to 14 million by 2050. AD is also the 6th leading cause of death in the US. In 2020, the cost of AD and other dementia in the nation was $305 billion (Alzheimer’s association, n/a). As is evident, the burden of AD and other dementia will continue to grow throughout the years which is why further research is critical to understand the underlying mechanisms and causes behind AD and other dementia. One important focus of public health is preventing disease and improving the quality of life of others. For my project, I am trying to address the potential applications of CRISPR gene editing to model and better understand AD and the possible implications that such research could have on future public health interventions towards treating AD.

Although my project is not directly related to public health, the research being done with my project has greater implications for the future of AD. If research on gene editing applications for AD progresses, in the future there could be effective treatments for AD patients that are completely gene-editing based. More research still needs to be done in regards to the effectiveness and safety of gene-editing to treat actual patients, but current research studies such as the project I was involved in are critical to furthering the current research on AD as we learn more about AD and inevitably what treatments will effectively work for it. Currently, AD mostly affects the older population so in the future as gene-editing studies progress, there could be potential public health interventions made available for AD patients through gene therapy. This type of public health intervention would be applied at the general population level after first going through clinical trials and being confirmed as safe and effective. Furthermore, my project ties into public health in that fAD occurs completely due to genetic mutations, so advancements in these types of research projects could lead to early identification of babies with genetic mutations for fAD and rapid treatment of it with gene-editing.

About the Freude lab

The Freude Lab is a neurodegenerative disease-focused research lab based in Copenhagen, Denmark led by head researcher Kristine Freude. The Freude Lab focuses on disease modeling using induced pluripotent stem cells (iPSCs) from patients and CRISPR-Cas9 gene editing (Frederiksen et al., 2019). The neurodegenerative diseases of focus are Alzheimer’s disease (AD) and Frontotemporal dementia (FTD). The main goal of the Freude lab is to utilize patient specific iPSCs and differentiate those cells into disease-relevant neuronal subtypes to investigate and further elucidate the underlying disease mechanisms.

What I did as a research assistant

Image of a healthy colony of stem cells

My time in the Freude lab was spent learning about Alzheimer’s disease (AD) and the potential applications of CRISPR-Cas9 gene editing in advancing the current research on AD. When I first joined the lab, I spent most of my time reading the current literature on AD, learning all about its pathophysiology, main target population, and current applications of gene editing that were being used to further study the disease. After becoming familiar with the literature I would begin my own research project under the guidance of a postdoctoral student in the Freude lab. For my research project, I focused specifically on familial Alzheimer’s disease (fAD) and using CRISPR-Cas9 gene editing to create a model of fAD using healthy stem cells. Specific point mutations in either the β-amyloid precursor protein (APP) gene, Presenilin-1 (PSEN1) gene, or Presenilin-2 (PSEN2) gene are known to lead to the development of fAD (Frederikson et al., 2019). So essentially my goal was to utilize CRISPR-Cas9 gene editing to introduce specific point mutations known to cause fAD into previously healthy cells to turn them into diseased fAD cells in order to further study those newly fAD cells.

Lessons learned

Image of Kristine Freude and her four undergraduate research assistants (including me)

From my project, I learned about the amazing potential that gene editing could hold in the future and how it could be applied to treat AD. Although extremely powerful, gene editing as an accurate and effective therapeutic tool is still in its infancy. Realistically we are still many years of research away before gene editing interventions can begin to be applied at a general population level but that is not to say that advancements being made currently are in any way insignificant or too slow. This project has provided me the opportunity to dive deeper into gene editing and how it can intersect with public health. This project has shaped my future plans in that I can take my previous interests in research and AD and be able to apply them in the context of public health. After Macalester, if I decide to pursue a career in research, I can also branch out into the public health sector.

References

Alzheimer's Association, n/a. “What Is Dementia?” Alzheimer's Disease and Dementia, 0AD, www.alz.org/alzheimers-dementia/what-is-dementia.

Frederiksen, H. R., Holst, B., Ramakrishna, S., Muddashetty, R., Schmid, B., & Freude, K. (2019). Generation of two iPSC lines with either a heterozygous V717I or a heterozygous KM670/671NL mutation in the APP gene. Stem cell research, 34, 101368. https://doi.org/10.1016/j.scr.2018.101368

Tcw, J., & Goate, A. M. (2017). Genetics of β-Amyloid Precursor Protein in Alzheimer's Disease. Cold Spring Harbor perspectives in medicine, 7(6), a024539. https://doi.org/10.1101/cshperspect.a024539

Wu, Y. Y., Chiu, F. L., Yeh, C. S., & Kuo, H. C. (2019). Opportunities and challenges for the use of induced pluripotent stem cells in modelling neurodegenerative disease. Open biology, 9(1), 180177. https://doi.org/10.1098/rsob.180177

Image Credits:

Brain Image by NewAtlas, https://newatlas.com/alzheimers-amyloid-beta-proteins-outside-brain/51999/

Tenzin Dothar

My name is Tenzin and I am a senior biology major with a community and global health concentration from Broomfield, Colorado. I am interested in studying public health and how that intersects with more clinical research, specifically looking at neurodegenerative diseases. Outside of classes I enjoy hiking, playing basketball and watching Planet Earth.

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