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  • Amelia Tai

Hope amidst the uncertainty of Alzheimer’s Disease

Updated: Mar 18, 2023

Edited by Eldrian Tho.


It is undeniable that the cognitive ability of humans is significant. How we learn and think is governed by our cognitive ability. According to studies, cognitive ability can be classified into four categories which are perception: the interpretation of what is sensed, attention: the ability to filter out unwanted stimuli, memory: the storing and retrieval of knowledge, and logical reasoning: coming up with a conclusion based on rational thinking. (1) However, the development of certain neurocognitive diseases such as Alzheimer’s disrupts the ability to learn or interpret information and gives rise to behavioural changes, impeding one’s daily life. An Alzheimer’s patient may forget events, misplace items due to memory impairment, and find it difficult to express his or her opinions. Occasionally, poor judgement will follow, restricting one's independence in managing daily tasks. (2)


Before delving into the possible solutions and treatments for Alzheimer’s disease, let’s look at our current level of understanding of the causes of this neurodegenerative disorder. Toxic proteins like insoluble beta-amyloid and tau aggregate to form plaques and neurofibrillary tangles around brain cells. (3) This phenomenon disrupts the transmission of signals between brain cells, leading to the degeneration of neuron cells. Hence, the brain shrinks, starting with the hippocampus¹ which is vital for learning and memory.


Figure 1: Inside the brain of an Alzheimer’s patient What happens in the brain of an Alzheimer’s patient? The Fisher Center for Alzheimer's Research Foundation (2010). https://www.alzinfo.org/articles/what-happens-to-the-brain-in-alzheimers-disease/ The blue and black areas in the right image indicates reduced brain activity as a result of Alzheimer’s.

Research has allowed us to understand that mutation contributes to the development of Alzheimer’s. A variation of the gene, APOE e4, increases the risk of Alzheimer's disease. Amyloid precursor protein (APP)² is present in all individuals. Nevertheless, in patients with Alzheimer’s disease, APP is abnormally cleaved by β- and γ-secretase enzymes to generate insoluble 4-kDa peptides, which are beta-amyloid plaques. Amyloid plaque may also build up in younger patients due to gene mutations of APP, PSEN1, or PSEN2, resulting in the build-up of toxic proteins. Furthermore, cardiovascular disease, brain injury, and age may also be risk factors for Alzheimer’s as brain cells may be progressively damaged as a consequence. (4)


In recent years, there has been considerable interest revolving around the emerging concept of mesenchymal stem cell (MSC)³ therapy, which can act as a potential treatment for Alzheimer’s. A new sense of hope has been kindled by the encouraging findings of current research. MSCs can be obtained from various tissues including bone marrow, umbilical cord blood, and amniotic fluid. MSCs can differentiate into specialised cells such as neuronal cells, chondrocytes, or adipocytes. It is currently also used to successfully treat autoimmune diseases and degenerative diseases such as diabetes, cartilage disease and COPD due to their ability of multi-differentiation and inflammation regulation. (5)


MSCs are able to improve functional memory by replacing damaged neurons with healthy cells and regenerating neurons as MSCs are pluripotent stem cells that undergo self-renewal and multidirectional differentiation. It can repair and regenerate injured cells or tissues through stem cell transplantation. In the case of Alzheimer’s, MSCs can differentiate into Schwann cell-like cells⁴, which can prevent the development and mitigate the symptoms of the disease. (6)


Extracellular vesicles (EVs) called exosomes and cytokines that are secreted from MSCs have also been shown to induce immunomodulatory⁵ and neuroprotective effects. The EVs help transmit messages across neuronal cells, promoting the growth of neurons as well as saving learning disabilities and improving functional recovery. Simultaneously, cytokines are growth factors that control the activity of the cells in the immune system or suppress immune responses. Its primary function is to regulate inflammation. Furthermore, MSCs inhibit T-cell⁶ proliferation and downregulate proinflammatory cytokines produced by macrophages, leading to immunomodulatory and anti-inflammatory effects. (7) The secretion of neurotrophic factors controls the differentiation and multiplication in the nervous system. This overcomes apoptosis, particularly the death of neurons, induced by the aggregation of beta-amyloid and tau proteins in Alzheimer’s. Thus, it improves the growth and survival of neurons, which in turn improves learning and memory ability. MSCs also synthesize proangiogenic factors, which stimulate the formation of new blood vessels to restore blood supply to recover damaged tissues in the brain. (8)


What makes it more ideal and promising compared to other types of stem cells? These cells have low tumorigenicity, meaning there is a low risk of MSCs differentiating into cancer cells. MSCs also have low immunogenicity⁷ as they are derived from the patient’s own body, unlike other stem cells that are collected from donor cells, so it eliminates the risk of rejection by the immune system. The low chance of immune rejection is also due to its immunosuppressive properties as discussed earlier. MSCs have shown the ability to avoid a negative response from a person’s immune system, allowing the cells to be transplanted in a wide range of people. This is great news as it will increase the accessibility of treatments without having to rely on the availability of donor stem cells. There are also no ethical concerns as they are adult stem cells. MSCs are not sourced from embryonic material.


On the downside, patients who are transplanted with MSC often undergo long-term chemotherapy or radiotherapy, so their immune system does not work properly, which may be associated with the risk of tumorigenesis. This may promote tumour growth when cells start to divide uncontrollably. Besides, the immunosuppression level of MSCs cannot be controlled, so MSC therapy may compromise the host’s defence against infectious agents Moreover, stem cell numbers and effectiveness begin to decrease as we age or suffer from other diseases, so the therapy may have little to no effect. (9)


At the end of the day, medical professionals still have to weigh the benefits and risks of various treatments such as MSC stem cell therapy for different individuals to determine which is most suitable for the patient’s condition. While the progress of research on MSCs continues, we should embrace the fact that the light is at the end of the tunnel. If we are able to manipulate stem cells to our benefit, many treatments can be attained.


 

Glossary:

  1. Hippocampus- a complex part of the brain found in the temporal lobe that regulates learning and memory related to facts, events and directions. It is responsible for converting short-term memory to long-term memory that will be stored in other parts of the brain; hence, it explains the loss of short-term memory in Alzheimer’s patients.

  2. Amyloid precursor protein (APP)- An integral membrane protein expressed in tissues mainly found in the synapses of nerve cells. It functions as a cell surface receptor that regulates synapse formation and ensures neuronal survival.

  3. MSCs- adult stem cells isolated from different sources and can differentiate into many different cell types within the body. The number and effectiveness decline as we age.

  4. Schwann-cells- Cells in the peripheral nervous system that produce the myelin sheath around neuronal axons. It helps to insulate and maintain nerve cells.

  5. Immunomodulatory- The suppression or activation of the immune system.

  6. T-cell- part of the immune system that is responsible for protecting the body from infections.

  7. Immunogenicity- The ability of a foreign substance to stimulate an immune response.

 

Reference:

  1. du Plessis, S., 2022. Cognitive Skills: What They Are, Why They Matter, How to Improve - Edublox Online Tutor. https://www.edubloxtutor.com/cognitive-skills/

  2. Alzheimer's disease - Symptoms and causes. (2022, February 19). Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/symptoms-causes/syc-20350447#:~:text=Overview,person's%20ability%20to%20function%20independently.

  3. Alzheimer's disease - Causes. (n.d.). NHS https://www.nhs.uk/conditions/alzheimers-disease/causes/#:~:text=Alzheimer's%20disease%20is%20thought%20to,form%20tangles%20within%20brain%20cells.

  4. Alzheimer's Disease and Stem Cell Therapy (2014, March 27). PMC. NCBI. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3984956/

  5. What are mesenchymal stem cells (MSCs)? (2022, September 5). DVC Stem. https://www.dvcstem.com/post/what-are-mesenchymal-stem-cells

  6. Jiang, K., Zhu, Y., & Zhang, L. New Prospects for Stem Cell Therapy in Alzheimer's Disease. (2021, November 24) IntechOpen. https://www.intechopen.com/chapters/78766

  7. Types of Mesenchymal Stem Cells (MSCs) and their Mechanisms of Action. (2022, September 5). DVC Stem. https://www.dvcstem.com/post/mscs

  8. Semedo, P., Burgos, M., Donizetti, C., & Olsen, N. How do Mesenchymal Stem Cells Repair? (2011, August 23) IntechOpen. https://www.intechopen.com/chapters/18220

  9. The Pros and Cons of Mesenchymal Stem Cell-Based Therapies. (2019, Apr 24) NCBI. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719501/

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