THE ROLE OF STEM CELLS IN TREATING ALZHEIMER’S DISEASE
By Vithusan Kuganathan
Stem cells are essentially cells that are undifferentiated. This means that they haven’t undergone differentiation yet, a process which enables them to develop some sort of specialism. If you consider a root hair cell – it has specific adaptations which complement its function. A stem cell hasn’t undergone this process meaning it has several potential applications in medicine – ranging from regenerative medicine in the spinal cord to treating neurodegenerative diseases like Alzheimer’s.
There are 3 main types of stem cells which broadly defining their ability to differentiate. These are pluripotent, multipotent and unipotent. Pluripotent refers to a stem cell’s ability to differentiate into any cell. These can often be found in the meristems of a plant. Multipotent refers to a stem cell being able to differentiate into certain types of cells, often based on their location, such as haematopoietic stem cells, “haema-” commonly referring to the blood. The location-based differentiation of this kind of stem cell is often referred to as a stem cell niche. Embryonic stem cells are often pluripotent, whilst adult stem cells tend to be multipotent and can be sub-classified as: haematopoietic, mesenchymal (responsible for bone cells, such as osteocytes and osteoblasts; cartilage cells, e.g. chondrocytes, etc.), neural stem cells (responsible for nerve cells, as well as cells that are not neuronal-based – astrocytes and oligodendrocytes/Schwann cells), epithelial cells (needed for cells lining the digestive tract, e.g. goblet cells) and skin cells (such as keratinocytes). These are some examples of the adult stem cells that exist. I’ve just unloaded a lot of jargon on you, but the main takeaway idea is that stem cells are really amazing features that can differentiate into what the body needs at any particular time.
Neuronal stem cells are of particular importance in treating Alzheimer’s. Alzheimer’s disease is a neurodegenerative disease and is the most common form of dementia. It is mainly characterised by a person losing their memories, but often has a differential impact on different memories. An analogy for this would be if you think of a bookshelf. If you shake the bookshelf – books on the top shelf (recent memories) are more likely to fall off in comparison to books on the bottom shelf (older memories). Alzheimer’s can have several symptoms and its symptomatology progressively worsens with time. Symptoms can range from aphasia to memory loss and a general loss of autonomy in one’s day to day life. It’s such a devastating disease as one can lose memory of their loved ones, or even themselves, essentially stripping them of their identity.
But what exactly causes Alzheimer’s?
Figure 1 - A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. A diagram coming from the aforementioned article.
As with many different diseases, there are different hypotheses as to the cause of this disease. One of the main ones is the amyloid hypothesis. Amyloid and tau are both proteins that can either kill neuronal cells or inhibit signalling between neurons. The breakdown of amyloid precursor proteins released β-amyloid proteins, which binds to LilrB2, then aggregates to form plaques. With the inhibition of this regulator of synaptic plasticity, there is a cascade of biochemical activity, culminating in the destruction of synapses. Without synapses, you lose a vital part of the Central Nervous System (CNS), whereby signals cannot be transferred from the axon terminal to the subsequent dendrite. This can affect various processes – such as long-term potentiation in the hippocampus, which can then cause a loss of memory, which has become synonymous with dementia. Another molecule, tau, has also been implicated in dementia. A hyperphosphorylated form of tau has been noted to cause neurodegeneration, whereby microtubule formation is inhibited, and you get neurofibrillary tangles, as seen in the diagram. Microtubules when functioning in their normal capacity, aim to transport nutrients from one part of a nerve cell to another. This reinforces a key biological concept of compartmentalisation in order to conserve space. This can be from the cell body to the synapse for neurotransmitter release for example. However, when the hyperphosphorylated form of tau aggregates and you get these neurofibrillary tangles, you don’t get the same transport of necessary nutrients, which can then lead to cell death, or inhibited functioning. This is because one of the key functions of a nerve cell is transmitting a signal, which relies on neurotransmitter release. For example, it requires ATP for exocytotic release of neurotransmitters contained within vesicles. This exemplifies an important chemical requiring transport in synaptic transmission.
Overall, the presence of plaques causes neuronal death – leading to dementia in some capacity. But, how do we potentially tackle it? That’s where stem cells come in. Adult hippocampal neurogenesis is a potential mechanism for combatting the initial amnestic effects of Alzheimer’s. This can be done through neural stem cells, whereby you upregulate resident neural stem cell niches, leading to greater neural cell production within the hippocampus. There have been proposed ways of upregulating the neurogenesis: either pharmacologically or through gene therapy introducing various growth factors to the brain including but not limited to: brain derived neurotrophic factor (BDNF), nerve growth factor (NGF), etc. This is more of a combative measure to reduce the extent of the progression of the disease. This is an example of endogenous repair.
Another way of treating Alzheimer’s is through exogenous repair. Contrastingly, it introduces new chemicals into the brain as opposed to upregulating the body’s natural production of them. Two of the main stem cell types being looked into are: iPSC (induced pluripotent stem cells) and NSC (neural stem cells). The introduction of the NSC’s causes increases neurogenesis, decreases neuroinflammation, as well as attenuates tau and β-amyloid, reducing Alzheimer’s neuropathology. Evidence for this lies in studies to reverse cognitive deficits, as well as release more immune modulatory factors. This has been seen in mice but is proof-of-concept. iPSC-derived neurons can be used in forming functional and active synaptic networks, reversing cognitive deficits. These studies are mostly in-vitro and as a result, can’t be used as the be-all and end-all of Alzheimer’s treatment.
To conclude, stem cells offer a promising path for progressing treatment into the future and their applications to other such neurodegenerative disease. As of now, many studies are looking into for proof-of-concept and are focussing on the potential neurotoxic side effects, because whatever the outcome, you are playing with one of the most delicate and intricate organs within the brain. So many variables have to be accounted for, however, stem cell research is definitely increasing in profile.
If you’re interested have a look at some of the sources I used for more insight into this topic. This article hardly does justice to the minutiae and significance of the topic.
Sources:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5427593/
ncbi.nlm.nih.gov/pmc/articles/PMC3090074/pdf/nihms288823.pdf
https://www.nature.com/articles/s41582-018-0116-6
https://www.nia.nih.gov/health/what-happens-brain-alzheimers-disease