About the Project
Advances in stem cell biology have enabled new methodologies with the unique ability to manipulate the human central nervous system (CNS), and have allowed the exploration of cell health and disease modeling with greater relevance to human tissue than previously possible. Amyloid precursor protein (APP) is a transmembrane protein found in many cell types around the body, most notably in brain cells such as neurons and synapses. APP processing is crucial to brain health. APP cleavage can be initiated by two different enzymes. One liberates a neuroprotective protein fragment, while the other causes protein fragments that are involved in neurodegeneration to be formed. We have developed a model cell system using induced Pluripotent Stem Cell (iPSC) derived cortical neurons. Using these cells we have been able to establish the presence of APP, and both enzymes involved in the fate of APP (the α -secretase ADAM10 and the β-secretase BACE-1).
We now need to understand much more about this processing pathway to properly understand the factors that affect brain health. We don’t yet know what factors influence which secretase is more active, for example. Studies have shown that lifestyle factors can affect the activity of secretase enzymes. For example, exercise can increase the activity of ADAM10. Diet may also affect secretase activity, as can drug use. Considering that all of these factors affect metabolism, it is highly likely that the metabolic state of the cell will affect secretase activity. If we are able to understand more about APP processing, better characterise protein interactions within the cell and establish the effect of metabolic flux and subsequent shift in redox status in the cell, we will learn more about the factors that can drive neuroprotection and ultimately brain health.
In this project, you will use human iPSC-derived neuron and astrocyte co-cultures to characterise the APP processing pathway. You will investigate potential factors that might influence the activity of the different secretase enzymes. You will investigate the conditions that affect APP processing to understand how APP processing could be manipulated to benefit brain health in humans.
This project is funded by the MIBTP Doctoral Training Partnership. MIBTP is a BBSRC funded Doctoral Training Partnership (DTP) between the University of Warwick the University of Birmingham, the University of Leicester, Aston University and Harper Adams University. For more information, please visit: https://www.birmingham.ac.uk/research/activity/mibtp/index.aspx