Age, diabetes and having the two copies of the gene for apolipoprotein E 4 (APOE ε4) are just some of the factors that significantly increase the chance of developing Alzheimer’s disease later on in life. Associate Professor Carmela Matrone’s research group used stem cells generated from Alzheimer’s disease patients with the APOE ε4 gene to show that this genetic risk factor is connected to a deterioration of a relationship between two key proteins, sortilin-related receptor (SORL1) and amyloid precursor protein (APP) 1 .
This work highlights exciting research advances in stem cell biology, as it is possible to create relevant human models of Alzheimer’s disease that not only replicate the end stages of the disease but allow for the study of the development and progression of the disease in a dish . Using a relevant human model improves on using animal models to investigate Alzheimer’s disease, as the research findings are more translatable and relevant aiding the search for new therapeutic targets.
Understanding Alzheimer’s Disease
Dementia itself is not a disease but an umbrella term for a collection of symptoms such as forgetfulness, disorientation, difficulties with problem-solving and communication.
Alzheimer’s disease is the most common cause of dementia symptoms affecting around 500,000 people in the UK 2 and 5 million in the USA 3 . The decline in memory in Alzheimer’s disease sufferers is largely due to the gradual degeneration of cells within the brain called neurons. In a healthy brain neurons actively talk to each other to create and retrieve memories however in an Alzheimer’s disease brain the communication between cells breaks down. This degeneration of neurons is primarily thought to be caused by the presence of two proteins, amyloid-β (Aβ) and tau. Making these key targets for the development of treatments .
Stem cells have the potential, under the right conditions, to become any type of cell . Axol Bioscience specialize in taking fully developed adult cells, such as skin cells or blood cells, and reprogramming them to stem cells . These stem cells are then programmed into a different specialized adult cell such as a heart cell or a brain cell. Stem cells have the potential to provide physiologically relevant models for diseases when adult cells from patients with different diseases such as Alzheimer’s disease, Parkinson’s disease or epilepsy are used.
Neural stem cells are an excellent model for yielding new insights into the mechanisms that may lead to Alzheimer’s disease
The amyloid precursor protein (APP) is the source of Aβ and can be chopped up in different ways either to produce Aβ or a non-toxic protein, therefore APP is another key player in the development and treatment of Alzheimer’s disease. It is known that APP travels widely in neurons to be processed in different areas but how APP moved around was largely unknown until recently. A protein called SORL1 acts a taxi for APP within neurons, when APP gets into the taxi it can be transported around the cell .
Using neural stem cells from Axol Bioscience, a recent study conducted by Prof. Matrone at Aarhus University in Denmark identified that in cells generated from patients with two copies of the APOE ε4 gene, levels of SORL1 were decreased 1 . Whereas in the neural stem cells with inherited mutations, that are known to cause familial Alzheimer’s disease, resulted in no changes of SORL1. The lack of correlation between SORL1 levels in neural stem cells from familial and sporadic (non-inherited) Alzheimer’s disease highlights the differences in what may cause the breakdown of communication in the Alzheimer’s disease brain .
More importantly, the relationship between APP and SORL1 in neural stem cells with the APOE ε4 gene was found to deteriorate and levels of Aβ were increased in comparison to neural stem cells from healthy donors and donors with familial Alzheimer’s disease. This deteriorating relationship between SORL1 and APP impacts on how APP travels around the neuron. By failing to interact with SORL1, APP ‘gets in with a bad crowd, in a bad neighbourhood’ which results in the generation of toxic A. The scientific understanding is that A then builds up in neurons over time which damages the neurons and causes the degeneration noted in Alzheimer’s disease.
Associate Prof. Matrone was able to salvage the relationship between APP and SORL1 and increase SORL1 levels by applying a chemical that stops the cutting of APP. Consequently, Associate Prof. Matrone has found a potential therapeutic target if the relationship between SORL1 and APP can be maintained and levels of SORL1 can be upheld this could reduce the accumulation of toxic Aβ by allowing the transportation of APP around neurons . This research shows that neural stem cells generated from Alzheimer’s disease patients are an excellent model for yielding new insights into the mechanisms that may lead to Alzheimer’s disease. This is the first step into identifying and validating a new therapeutic target.
Axol Bioscience supply a wide range of human neural stem cells from Alzheimer’s disease patients who either have the inherited genetic mutations that lead to Alzheimer’s disease ( ax0112 PSEN1-L286V , ax0113 PSEN1-M146L , ax0114 PSEN1-A246E , ax0115 PSEN2-N141I ) or the gene APOE ε4 ( ax0111 APOE4 HOM ) all featured in this publication.
1. Zollo A, Allen Z, Rasmussen H et al., Sortilin-Related Receptor Expression in Human Neural Stem Cells Derived from Alzheimer’s Disease Patients Carrying the APOE Epsilon 4 Allele. Neural Plasticity (2017)
2. Alzheimer's Research UK. (2017). Alzheimer's disease. [online] Available at: http://www.alzheimersresearchuk.org/wp-content/uploads/2015/01/ALZ040-What-is-Alzheimers_WEB-.pdf [Accessed 5 Aug. 2017]
3. Latest Facts & Figures Report | Alzheimer's Association. (2017). Latest Alzheimer's Facts and Figures. [online] Available at: http://www.alz.org/facts/overview.asp [Accessed 5 Aug. 2017].