Alzheimer’s disease can cause gradual memory loss, dementia and death, altering the lives of the individual and those around them. Currently there are only very limited treatments, mainly acetylcholine inhibitors which boost the activity of the neurones affected in the CNS by the Alzheimer’s pathology. These treatments do not affect progression of the disease and are often only affective for short periods of time, bring their cost-effectiveness into question1.
One of the reasons for the lack of effective long term treatment for this disease comes from the poor modelling techniques that have currently been available; because of the neurological nature of the disease, access to living tissues on which to experiment has been understandably limited. The lack of suitable tissue confines study in many instances to post-mortem tissue and animal models which are generally unideal, particularly for large scale drug screening which would help to identify possible therapeutics and molecular mechanism investigation which could identify potential drug targets2.
The recent development of induced pluripotent stem cells (IPSCs) generated from human dermal fibroblasts in 20073 has created a new and incredibly useful tool for studying Alzheimer’s pathology on a cellular level; it also bypasses many of the tricky ethical issues of using human embryonic stem cells since IPSCs can be generated from the cells of living adults. What the process of reprogramming a human fibroblast achieves is the generation of a self-renewing, pluripotent and easily accessible cell which can be turned into multiple different cell types. In the case of Alzheimer’s disease, these IPSCs can be made from a cell from a patient with AD and then differentiated into a neurone, the cell type affected in the condition. This AD-IPSC can then be compared to an IPSC from a non-affected individual and the differences can be highlighted and investigated; this is the route which research is now taking4.
Using IPSC technology, it has been discovered that there is an accumulation of the protein A-beta which is secreted from AD neurones in greater amounts than in unaffected neurones5; studies have also produced data suggesting that the products of the enzyme APP are involved in Alzheimer’s pathology, an enzyme closely related to A-beta production6. Other studies have shown an increase in the accumulation of large endosomes, a process seen in cells taken from individuals with Down’s syndrome4. Essentially, IPSC technology has revealed multiple alterations occur on a cellular level that are likely to lead to reduced neuronal function and Alzheimer’s pathology.
Drug screening has also been carried out in recent studies, testing gamma-secretase inhibitors, beta-secretase inhibitorrs and NSAIDs (the drug group to which painkillers ibuprofen and aspirin belong) on their ability to reduce A-beta secretion in IPSC-derived neurones. The results have come back positive, especially concerning gamma-secretase inhibitors and NSAIDs which were shown to significantly decrease the levels of A-beta secretion; they were also shown to not kill the cells even at the highest concentrations studied7.
However, this does not mean that taking aspirin will cure Alzheimer’s disease; there are still many more questions to be asked and much more to find out about the mechanisms of the disease and drug actions before any safe drugs will be put into clinical trials. IPSCs can only show cellular models and drugs that have an effect on a single IPSC-derived neurone are likely to have an effect in other cells around the body; a drug cannot go directly from cell model to human because of the very high risk of side effects. There are also multiple other molecular aspects of the disease which have not been investigated fully so there may be other potential drug targets which are more specific to neurones affected in AD, making treatment much more specific. IPSC technology does, however, have great potential for Alzheimer’s disease modelling8.
In review, IPSC technology is aiding the investigation into Alzheimer’s disease and is heading research in the right direction. However, it is likely to be some time before a treatment based on this research is used in the clinic.
Cholinersterase inhibitors for the treatment of Alzheimer’s disease.
2 – Khachaturian et al, 2012, Perspectives on Alzheimer’s disease; Past, present and future, Advances in Biological Psychiatry, 28:179-188.
3 – Takahashi et al, 2007, Induction of pluripotent stem cells from adult human fibroblasts by defined factors, Cell, 131:861-872
4 – Israel et al, 2012, Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells, Nature, 482:216-220
5 – Yahata et al, 2011, Anti-A-beta drug screening platform using human IPSC-derived neurones for the treatment of Alzheimer’s disease, PLoS One, 6:e25788
6- Koch et al, 2012, Presenilin-1 L166p mutant human induced pluripotent stem cell-derived neurones exhibit partial loss of gamma-secretase activity in endogenous amyloid-beta generation, American Journal of Pathology, 180:2404-2416
7 – Yagi et al, 2011, Modelling familial Alzheimer’s disease with induced pluripotent stem cells, Human Molecular genetics, 20:4530-4539
8 – Gao et al, 2013, Potential Therapeutic applications of differentiated induced pluripotent stem cells (IPSCs) in the treatment of neurodegenerative diseases, Neuroscience, 228:47-59