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IPSCs as a model to study APP processing

Project Description

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 an α –secretase (ADAM10) enzyme and if this is the case then this pathway liberates a neuroprotective amino terminal fragment (sAPP-α). Alternatively APP can be cleaved by a β-secretase enzyme (BACE-1). When this happens, protein fragments that are involved in neurodegeneration are 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, the α -secretase ADAM10 and the β-secretase BACE-1. However, we need to understand much more about this processing pathway to properly understand the factors that affect brain health. We don’t yet know what influences 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.

It is also known that ADAM10 activity is regulated by a family of glycoproteins called tetraspanins. Tetraspanins form networks and interactions can associate with ADAM10 to regulate its substrate specificity and 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 activity of the different secretase enzymes. You will characterise tetraspanins in iPSCs and examine the interaction of tetraspanins with the APP processing pathway. You will investigate the conditions that affect APP processing to understand how APP processing could be manipulated to benefit brain health in humans.

Funding Notes

This project is funded by the BBSRC as part of the Midlands Integrative Biosciences Training Partnership.
More details on how to apply and the MIBTP programme here:
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