Understanding Alzheimer's Disease Mechanisms

Factors that increase the chance of developing Alzheimer’s disease later in life include diabetes, age and having two copies of the gene for apolipoprotein E 4 (APOE ε4).

A research group led by Associate Professor Carmela Matrone used stem cells generated from patients with Alzheimer’s disease with the gene APOE ε4, to show that this genetic risk factor is connected to a deterioration of a relationship between two critical proteins: amyloid precursor protein (APP) and sortilin-related receptor (SORL1)1.

This research demonstrates exciting advances in stem cell biology, proving that it is possible not only to create relevant human models of Alzheimer’s disease that replicate the end stages of the disease, but also allowing the development and progression of the disease to be studied in a dish. This is an improvement on the use of animal models because findings are more relevant and translatable. Results also aid the search for new therapeutic targets.

Understanding Alzheimer’s Disease

Dementia is not a disease in itself, but rather an umbrella term for a collection of symptoms including disorientation, forgetfulness, and difficulties with communication and problem solving.

The most common cause of dementia is Alzheimer’s disease and it affects around 500,000 people in the UK2 and five million in the USA3. Patients with Alzheimer’s disease suffer a decline in memory and this is mainly due to the gradual degeneration of neurons, which are cells within the brain.

Neurons actively talk to each other to retrieve and create memories in a healthy brain. However, in Alzheimer’s disease, there is a breakdown in communication between cells. This degeneration of neurons is thought to be primarily caused by the presence of two proteins called tau and amyloid-ß (Aß). Therefore, these proteins are key targets for the development of treatments.

Understanding Stem Cells

Under the right conditions, stem cells have the potential to become any type of cell. Scientists at Axol Bioscience specialize in reprogramming fully developed adult cells, for example blood or skin cells, into stem cells. These stem cells can in turn be programmed into different specialized adult cells, for example a brain cell or a heart cell. When adult stem cells from patients with different diseases such as Parkinson’s disease, epilepsy or Alzheimer’s disease are used, stem cells have the potential to create physiologically relevant models for these diseases.

Understanding the Mechanisms that May Lead to Alzheimer’s Disease with Neural Stem Cells

The amyloid precursor protein (APP) is a key component for the development and treatment of Alzheimer’s disease because it is the source of Aß and can be chopped up in different ways, producing either Aß or a non-toxic protein. It is understood that, in order to be processed in different areas, APP travels widely through neurons. Until recently however, the way in which APP moved around was largely unknown. Within neurons, a protein called SORL1 acts as a taxi for APP. Once the APP gets into the taxi, it can be transported around the cell.

A recent study conducted by Prof. Matrone at Aarhus University in Denmark used neural stem cells from Axol Bioscience to identify that cells generated from patients with two copies of the APOE ε4 gene had decreased levels of SORL11. The differences that may cause the breakdown of communication in the Alzheimer’s disease brain are highlighted by the lack of correlation between SORL1 levels in neural cells from familial and sporadic (non-familial) Alzheimer’s disease.

Moreover, in comparison to neural stem cells from healthy donors and donors with familial Alzheimer’s disease, the relationship between APP and SORL1 in neural stem cells with the APOE ε4 gene was found to deteriorate and Aß levels were increased. Movement of APP around the cell is impacted by the deteriorating relationship between SORL1 and APP. Toxic A is generated when APP fails to interact properly with SORL1. It is thought that a build-up of A in neurons over time damages them and causes the degeneration seen in Alzheimer’s disease.

By applying a chemical that stops the cutting of APP, Associate Prof. Matrone salvaged the relationship between SORL1 and APP and increased levels of SORL1. If the relationship between SORL1 and APP can be maintained and SORL1 levels can be upheld, the APP could be transported around the cells, so reducing the accumulation of toxic Aß. This would mean that Associate Prof. Matrone has found a potential therapeutic target.

This research demonstrates that neural stem cells generated from Alzheimer’s disease patients are a brilliant model for providing new insights into the mechanisms that might underpin Alzheimer’s disease. This understanding is the first step to identifying and validating new therapeutic targets.

References

  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].

About AXOL Biosciences

Axol specializes in human cell culture.

Axol produces high quality human cell products and critical reagents such as media and growth supplements. We have a passion for great science, delivering epic support and innovating future products to help our customers advance faster in their research.

Our expertise includes reprogramming cells to iPSCs and then differentiating to various cell types. We supply differentiated cells derived from healthy donors and patients of specific disease backgrounds. As a service, we also take cells provided by customers (primary or iPSC) and then do the reprogramming (when necessary) and differentiation. Clearly, by offloading the burden of generating cells, your time is freed up to focus on the research. Axol holds the necessary licenses that are required to do iPSC work.

The package wouldn't be complete without optimized media, coating solutions and other reagents. Our in-house R&D team works hard to improve on existing media and reagents as well as innovate new products for human cell culture. We also supply a growing range of human primary cells; making Axol your first port of call for your human cell culture needs.


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Last updated: Oct 15, 2019 at 4:16 AM

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