Written by Kimiya Mansour and edited by Alexander Alva
Photo by Google DeepMind
Patients with Alzheimer’s disease (AD), a progressive neurodegenerative disease, experience gradual impairments in both memory and cognitive abilities, which can significantly lower their quality of life. In 2020, almost 5.8 million American people were living with AD, with the disease predominantly affecting the 65-year-and-older population [2]. One type of AD, known as sporadic AD (sAD), occurs mostly due to a combination of gene interactions and environmental factors, such as lifestyle [1]. It has been projected that in 2060, almost 14 million people will have AD, leading to a huge call-for-action for providing an effective treatment for it [2].
Mice and other organisms with similar genetic characteristics to humans have been advantageous for studying AD—they allow researchers to replicate AD’s development and effects to understand the biological mechanisms involved. However, differences between induced AD (introducing a disease-inducing mutation) in mouse’s genes versus progression of AD in humans might be contributing to ineffective treatment for this disease. For example, although mice can be genetically modified to express human genes, there are inherent genetic differences between the species that cannot be accounted for [3]. Even though Aduhelm medication to treat AD is approved by the U.S. Food and Drug Administration (FDA), many researchers argue against its efficacy [5].
By using a brain organoid derived from human induced pluripotent stem cells (hiPSCs), researchers have designed a unique paradigm to investigate the abnormal function of sAD in humans [3]. HiPSCs are a particular kind of stem cell, which originate from somatic (non-reproductive) adult human cells and are reprogrammed (introduced to particular genes) to be pluripotent, or lead to any different cell type in the body [7]. Brain organoids are miniature, clustered stem cells that self-organize to mimic the developing human brain [6]. This allows researchers to have a humanistic model to induce sAD and study it.
However, brain organoids have limitations. For instance, organoids don’t have blood vessels [3]. As one of the main risk factors for sAD among aging human brains is blood leakage into the brain, researchers exposed their brain organoid to a serum to mimic the effect of this leakage to accurately depict sAD progression [3]. The serum accurately leads to hallmark AD pathology, such as synaptic loss (referring to neuronal connection severing that correlates to an AD patient’s memory loss) [3].
In conclusion, researchers have created a unique experimental model to depict the physiology of AD, overcoming differences between inducing AD versus the “normal” development of AD as well as differences in disease development between mice and humans. This, along with studying different neurodegenerative diseases, can positively influence future therapeutic measures for AD. But, it’s imperative to note that AD is a highly polygenic (i.e combination of many genes interacting with each other) disease and there has been reported cases of one’s environment and genetics leading to AD; therefore, it’s highly advantageous to offer a paradigm that accounts for the interactions of risk factors. Moving forward, hiPSC can be utilized to screen (check for its safety and efficacy) for various potential medications to treat/manage AD, and thus expedite FDA approval [4].
References
1. Alzheimer Society of Canada. (n.d.). Understanding genetics and Alzheimer’s disease. Retrieved May 6, 2023, from alzheimer.ca/sites/default/files/documents/research_ understanding-genetics-and-alzheimers-disease.pdf
2. Centers for Disease Control and Prevention. (2020, October 26). What is Alzheimer’s disease? Centers for Disease Control and Prevention. Retrieved May 4, 2023, from www.cdc.gov/aging/aginginfo/alzheimers.htm
3. Chen, X., Sun, G., Tian, E., Zhang, M., Davtyan, H., Beach, T. G., Reiman, E. M., Blurton-Jones, M., Holtzman, D. M., & Shi, Y. (2021). Modeling Sporadic Alzheimer’s Disease in Human Brain Organoids under Serum Exposure. Advanced Science (Weinheim, Baden-Wurttemberg, Germany), 8(18), e2101462.
4. Park, J. C., Jang, S. Y., Lee, D., Lee, J., Kang, U., Chang, H., Kim, H. J., Han, S. H., Seo, J., Choi, M., Lee, D. Y., Byun, M. S., Yi, D., Cho, K. H., & Mook-Jung, I. (2021). A logical network-based drug-screening platform for Alzheimer’s disease representing pathological features of human brain organoids. Nature Communications, 12(1), 280.
5. Reardon, S. (2023). FDA approves Alzheimer’s drug Lecanemab amid safety concerns. Nature, 613(7943), 227–228.
6. Xu, J., & Wen, Z. (2021). Brain Organoids: Studying Human Brain Development and Diseases in a Dish. Stem Cells International, 2021, 5902824.
7. Ye, L., Swingen, C., & Zhang, J. (2013). Induced pluripotent stem cells and their potential for basic and clinical sciences. Current Cardiology Reviews, 9(1), 63–72.