By Tara Nguyen, Human Development, ’25

Alzheimer’s disease (AD) is a neurodegenerative disease that causes cognitive and motor functions to worsen over time, eventually leading to the loss of day-to-day function [1]. AD is the fifth leading cause of death in individuals aged 65 and older. Other causes of death within the top five, such as stroke and cardiac arrest, have decreased in numbers since 2000 while deaths from AD have increased by over 145% [2]. In 2022, an estimated $321 billion was spent on long-term and hospice care for AD patients older than 65 years, an increase from $234 billion as recently as 2019 [1-2]. This piece will cover the pathogenesis of AD and how stem cell research is contributing to finding a successful treatment for AD.

One of the foremost signs in the pathogenesis of AD is the accumulation of amyloid-beta (Aβ) peptides, 39-43 residue amino acids derived from the irregular activity of the amyloid-beta precursor protein (APP) [3-4]. The Aβ peptide forms plaque deposits in areas of the brain that control memory function such as the medial temporal lobe and the neocortical structures [4-5]. The impacts of plaque deposits in these areas of the brain include impaired memory, attention, thought, and perception.

The other most common sign in the development of AD is the occurrence of neurofibrillary tangles (NFTs), which occur due to the misfolding of tau proteins. Tau is an important microtubule protein that takes on six distinct isotypes, each with its own precise function. This protein is important in maintaining the stability of the microtubule system, which contributes majorly to axonal transport [6]. In axonal transport, motor proteins use microtubule systems to transport proteins between neurons. Without stable microtubule systems for this transport, the development, function, and survival of nerves are inhibited [7]. Hyperphosphorylation of the tau protein leads to its overexpression and aggregation, meaning that the microtubule system which tau maintains will no longer be stable. This means that nerve transport, development, function, and survival will be impacted, and NFTs will propagate in the neuronal space of patients with AD. Furthermore, the overexpression of hyperphosphorylated tau proteins can lead to the damage and loss of neurons [6]. 

Most cells in the human body are specialized cells, such as those that make up the nervous system or the cells that function in the liver. However, there are cells that have regenerative abilities and, unlike specialized cells, are not restricted to one specific function: stem cells. Stem cells provide opportunities for research into regenerative medicine due to their ability to specialize into different cells of various functions rather than only into one. Specifically, multipotent stem cells (MSCs) can specialize into cells from one particular organ or system. For example, neural stem cells (NSCs) are MSCs in the central nervous system that have the ability to differentiate into all nervous system cells. While these cells are indeed stem cells, they only have the potency to specialize into neural system and related cells. 

In 2009, a study focusing on NSCs was completed at the University of California, Irvine’s Department of Neurobiology and Behavior Institute for Memory Impairments and Neurological Disorders by Mathew Blurton-Jones et al. This study used transgenic mice models that expressed features of Alzheimer’s Disease, such as pathogenic forms of APP and phosphorylated tau proteins [8]. However, instead of targeting these pathogenic hallmarks of AD, researchers transplanted NSCs into the hippocampus of these mice [8].

Despite there being no change to the amounts of APP present or the tangles in phosphorylated tau proteins, this study found that cognitive function of these mice improved through brain-derived neurotrophic factor (BDNF), which mediates the survival and growth of neurons in the central nervous system [8]. While the hallmarks of AD were still present in these mice, they were able to regain some cognitive function.

Another study done by I.S. Kim et al, in cooperation with the Yonsei University College of Medicine in South Korea in 2015, used stem cells to investigate potential therapeutic effects in AD. Like the study by Blurton-Jones et al, this study utilized NSCs in a transgenic mouse model. The transgenic mouse model had a neuronal disease state that resembles that of Alzheimer’s Disease with features including damaged neurons, an excess of APP, and phosphorylated tau proteins [9].

This study found that non-engineered human NSCs, when inserted into this transgenic mouse model, inhibited the phosphorylation of tau in the model by interfering with the related signaling pathways [9]. As previously discussed, the overexpression of phosphorylated tau is one of the causes of damaged neurons, a primary cause of AD. The researchers hope that a similar effect may show in humans, since the insertion of human NSCs into the transgenic mouse model was able to limit one of the factors and indicators of the development of AD [9].

Further studies are needed to determine whether or not stem cells can prove truly useful in the treatment of AD. Studies that have been approved and published thus far have shown a hopeful light towards the usefulness of stem cells in the modeling and treatment of AD. The works of Matthew Blurton-Jones et al. and I.S. Kim et al. provide a stepping stone towards a working treatment to inhibit, or even reverse, the effects of AD. Some next steps may include researching a possible solution for Aβ plaques, or finding solutions to consider both NFTs and Aβ plaques, and these studies may, hopefully, help the process of developing a successful treatment for AD in humans.

References:

1. “2019 Alzheimer’s Disease Facts and Figures.” Alzheimer’s & Dementia 15, no. 3 (2019): 321–87. https://doi.org/10.1016/j.jalz.2019.01.010. 
2. 2022 alzheimer’s disease facts and figures. (2022). Alzheimer’s & Dementia, 18(4), 700–789. https://doi.org/10.1002/alz.12638 
3. Breijyeh, Zeinab, and Rafik Karaman. 2020. “Comprehensive Review on Alzheimer’s Disease: Causes and Treatment” Molecules 25, no. 24: 5789. https://doi.org/10.3390/molecules25245789
4. Danielle G. Smith, Roberto Cappai, Kevin J. Barnham, The redox chemistry of the Alzheimer’s disease amyloid β peptide, Biochimica et Biophysica Acta (BBA) – Biomembranes, Volume 1768, Issue 8, 2007, Pages 1976-1990,ISSN 0005-2736, https://doi.org/10.1016/j.bbamem.2007.02.002. (https://www.sciencedirect.com/science/article/pii/S0005273607000387)
5. Rukmangadachar LA, Bollu PC. Amyloid Beta Peptide. [Updated 2022 Aug 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459119/
6. Cheng Ying, Bai Feng, The Association of Tau With Mitochondrial Dysfunction in Alzheimer’s Disease. Frontiers in Neuroscience, Volume 12, 2018, https://www.frontiersin.org/articles/10.3389/fnins.2018.00163     https://doi.org/10.3389/fnins.2018.00163, ISSN 1662-453X 
7. Sleigh, J.N., Rossor, A.M., Fellows, A.D. et al. Axonal transport and neurological disease. Nat Rev Neurol 15, 691–703 (2019). https://doi.org/10.1038/s41582-019-0257-2
8. Blurton-Jones, M., Kitazawa, M., Martinez-Coria, H., Castello, N. A., Müller, F.-J., Loring, J. F., Yamasaki, T. R., Poon, W. W., Green, K. N., & LaFerla, F. M. (2009). Neural stem cells improve cognition via BDNF in a transgenic model of alzheimer disease. Proceedings of the National Academy of Sciences, 106(32), 13594–13599. https://doi.org/10.1073/pnas.0901402106 
9. Lee, IS., Jung, K., Kim, IS. et al. Human neural stem cells alleviate Alzheimer-like pathology in a mouse model. Mol Neurodegeneration 10, 38 (2015). https://doi.org/10.1186/s13024-015-0035-6