Amyloid β clearance and neuronal function in a human model of Alzheimer's Disease

Type of project: Pilot project

What do we already know?

Build-up of the protein amyloid-beta in brain cells leads to dysfunction in their signalling, which can impair the integrity of circuits within the brain and cause cognitive failure. Normally, the production and clearance of amyloid-beta in the brain is balanced, however in Alzheimer’s disease the mechanisms of clearance are substantially reduced resulting in an abnormal accumulation of the protein.

A major mechanism for amyloid-beta clearance is through break-down by an enzyme called Neprilysin (NEP). NEP is therefore thought to be protective to brain cells against the toxicity caused by amyloid-beta build-up and may have therapeutic benefit to Alzheimer’s disease and other dementias.

What is this project trying to find out?

While NEP in known to break-down amyloid beta its role in the communication between neurons has not yet been explored.  The project will look at the link between the processing of amyloid precursor protein (APP) from which amyloid-beta is produced, the activity of NEP, and nerve cell communication via electrical signals.

How will they do this?

This project study human nerve cells which have been reprogrammed from the skin cells of patients with familial Alzheimer’s disease. These cells carry a mutation in preselin-1, a protein which processes APP cutting it to generate amyloid-beta. The expression of NEP in populations of nerves cells with different levels of APP processing will be compared and the resulting outcome on the cells physiology examined.

Genetic and pharmacological manipulations to enhance NEP activity will be employed to measure any resultant changes in amyloid-beta levels over time. This approach will also be used to establish if changing NEP alters communication and network connectivity within the nerve cell population.

Why is it important?

The project will provide a greater understanding of how nerve cell signals are disrupted during dementia. This study will provide important information required for the development of a novel therapeutic approach using NEP as a target for drugs against Alzheimer’s disease and other dementias.

Further information

Please click here for more information about the work of Dr Talitha Kerrigan