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Our brains are made up of a range of different brain cells, with different types occurring in different places. Neurodegenerative diseases like Alzheimer's and Parkinson's – two prevalent causes of dementia – usually begin by damaging specific brain cells. So, why is it that some brain cells are more susceptible than others to the toxic proteins associated with these conditions? One researcher in DPUK's Stem Cell Network is aiming to find out.

Ajantha AbeyAjantha Abey

Ajantha Abey is in the first year of his DPhil (PhD) at Oxford University. Originally from Australia, Ajantha studied for his undergraduate degree at the University of Sydney. He then completed a one-year research master's degree before becoming a research assistant in a lab using experimental stem cell therapy to treat dogs who have dementia.

When his lab was shut due to COVID-19, Ajantha came to England to complete his doctorate in the Department of Physiology, Anatomy and Genetics at Oxford University. Ajantha is using technology funded by DPUK as part of its Stem Cell Network to investigate why certain populations of brain cells are more susceptible to Alzheimer’s and Parkinson’s diseases.

Brain cell susceptibility

In Parkinson's disease, cells in a part of the brain called the substantia nigra are vulnerable to damage by the toxic protein alpha-synuclein, whereas brain cells in another part of the brain called the cortex remain intact. By contrast, in Alzheimer's disease, the brain cells in the cortex are damaged by toxic tau proteins, while brain cells in the substantia nigra are unaffected. This pattern occurs despite each toxic protein existing everywhere in the brains of people with that disease.

The different populations of cells that are affected by each disease gives rise to the difference in symptoms – people with Parkinson's mainly have movement issues while people with Alzheimer's have problems with thinking and memory. You can read more about the functions of different areas of the brain in our blog post, 'Brain areas decoded'.

Fascinated by why some cells are more vulnerable to these toxic proteins than others, Ajantha wondered whether this vulnerability is caused by a feature of the cells themselves or by things in their environment.

Disentangling the causes

Ajantha explained: 'It's really difficult to disentangle these two factors when looking at a whole brain or an animal model – this is where individual stem cells come in handy. They allow us to take out all the other factors that could be at play to hone down on whether something intrinsic about that cell that makes it more vulnerable to Alzheimer's or Parkinson's disease.'

Induced pluripotent stem cells (iPSCs) are living human cells that have the potential to grow into any cell type in the human body. Ajantha is growing these special cells into brain cells – a process called differentiation – from the cortex and the substantia nigra.

Image showing iPSC-derived stem cells from Parkinson's patients differentiating into cortical neuronsImage showing iPSC-derived stem cells from Parkinson's patients differentiating into cortical neurons

Growing only specific cells allows him to study the biological mechanisms at an individual cell level. Therefore, he can compare the differences between each cell type without interference from their environment.

Ajantha is using iPSC samples from patients with Alzheimer's disease and patients with Parkinson's disease so he can also compare the differences between cells affected by the two diseases.

Impact of toxic proteins

Another aspect of Ajantha's project will be to expose each of the brain cells to man-made versions of the toxic tau and alpha-synuclein proteins. He will then observe how these proteins affect cells differently in the two different diseases, as well as in the two different brain areas.

Image showing alpha-synuclein (red) accumulating in cortical neuronsImage showing alpha-synuclein (red) accumulating in cortical neurons

Once Ajantha has established whether cells from different brain regions are intrinsically more or less vulnerable to tau or alpha-synuclein, he will then look at why this might be the case. He suspects a biological pathway called the autophagy pathway might be to blame.

The autophagy pathway is a system of cell recycling, where waste products from brain cells are broken down and used to make different things the cell needs. Ajantha thinks this pathway may be less efficient in some cells and may become overwhelmed by a build-up of waste products.

Ajantha said: 'Once we can see a tangible difference between different brain cell types and understand what their vulnerable pathways are in Alzheimer's and Parkinson's, that really opens up possibilities for us to treat those diseases by helping boost the defective pathway in vulnerable cells.'

Ajantha says none of this would be possible without the DPUK-funded Stem Cell Network, which gives him access to the iPSCs to conduct his research. Being able to use cells from real patients with Alzheimer's and Parkinson's makes his research directly relevant to other people with these conditions.