Tracking amyloid-beta production in nerve cells

Lead Investigator: Dr Clare Futter
PhD student: James Edgar
Institution: University College London
Grant type: PhD studentship
Amount: £75,000  
Date started: October 2009
Date completed: September 2012


Scientific Title: The role of multivesicular endosomes in the generation of beta-amyloid in Alzheimer's disease.

What was the project, and what did the researchers do?

Amyloid-beta containing plaques are central to the pathology of Alzheimer's disease. The site within brain cells (neurones) where amyloid-beta is generated is not clear. Amyloid-beta is made by partial digestion of amyloid precursor protein (APP).

This PhD project has investigated the role of multivesicular bodies in APP trafficking and processing.  Multivesicular bodies (MVBs) are compartments within the cell, which have a number of functions, including the transport of proteins to compartments where they are degraded and the release of proteins from within the cell to the outside environment.

What were the key results and how will these help in the fight against dementia?

The researchers used cryo-immuno electron microscopy, a very powerful microscopic technique, to localise APP to internal vesicles within the lumen of a subpopulation of MVBs. They showed this first in cultured cell lines and then in nerve cells of the brain.

These internal vesicles can be formed by a number of distinct mechanisms. In cultured cells they were able to interfere with these different mechanisms and thus identify the machinery that sorts APP onto these internal vesicles.  Furthermore, they found evidence that the movement of APP onto these internal vesicles is a key step in the release of amyloid-beta from the cell. 

The researchers also found that amyloid-beta causes disruption of MVBs and lysosomes.  Lysosomes are compartments in the cell that function in degrading old or damaged proteins and they have shown that when they become full of amyloid-beta, they leak. This could be a potential way in which amyloid-beta causes neuronal death and dysfunction, leading to loss of neuronal connections and eventually dementia.

Understanding how and where amyloid-beta is generated within neurones and the effects of amyloid-beta accumulation on the cell increases our understanding of the biology of Alzheimer's disease and will help the development of potential therapeutics for Alzheimer's disease that can be targeted directly to the site of amyloid-beta production.

What happened next? Future work and additional grants

James Edgar has been awarded his PhD and has now commenced a postdoctoral position in the laboratory of Professor Margaret Robinson at the Cambridge Institute for Cell Biology Research.

How were people told about the results? Conferences and publications

Conferences

2010 Alzheimer's Society Research Conference - Warwick "Trafficking of the amyloid precursor protein through the endocytic system"

2010 Joint BSCB / BSDB meeting - Canterbury "Trafficking of the amyloid precursor protein through the endocytic system"

2010 UCL neurodegeneration seminar  -London "Trafficking of the amyloid precursor protein through the endocytic system"

2011 AAICAD (Alzheimer's Association International Conference on Alzheimer's Disease) - Paris "The role of multivesicular endosomes in the traffic of the amyloid precursor protein"

2011 Alzheimer's Society Research Conference- Birmingham "The role of multivesicular endosomes in the traffic of the amyloid precursor protein"

2011 Society for Neuroscience - Washington D.C - "The trafficking of the amyloid precursor protein through a subset of multivesicular endosomes"

2011 UCL neurodegeneration seminar  -London "The role of multivesicular endosomes in the traffic of the amyloid precursor protein"

Publications

Jul 2015 - Edgar et al,  "ESCRTs regulate amyloid precursor protein sorting in multivesicular bodies and intracellular amyloid-β accumulation." Journal of Cell Science 128(14):2520-8. doi: 10.1242/jcs.170233.  

James was also filmed for an Alzheimer's Society video and has appeared on Alzheimer's Society publicity material.