Functional proteomics for elucidating the mechanism of amyloid toxicity

Lead Research Organisation: King's College London
Department Name: Unlisted

Abstract

Alzheimer?s disease is a devastating condition that affects up to three quarters of a million people in the UK, representing ~1% of the population. Since this disease affects primarily older people and the number of people reaching an advanced age continues to increase each year, the proportion of affected people is rising. Some treatments for Alzheimer?s disease now exist, but all of these treat only the symptoms, and not the cause so that after a while the treatments fail and patients continue to deteriorate as nerve cells die and dementia worsens. One of the major changes in Alzheimer brain is the presence of neuritic or senile plaques, comprised mainly of a protein called amyloid. A second change is the appearance of tangles containing a different protein called tau. However, this project focuses on amyloid protein since the deposits of amyloid present in plaques are abnormal and it is important to determine how this abnormal form is generated from its precursor protein. A major site for the production of amyloid is in specialised areas on the surface of the nerve cell called lipid rafts. These rafts contain concentrations of molecules including proteins and cholesterol that ?float? around in the cell surface in a sea of fats. Our hypothesis is that changing the amount of cholesterol influences the composition of the proteins normally present in lipid rafts and this affects the production of amyloid protein. Such changes could trigger a series of signalling events through the cell that leads to nerve cell death and ultimately dementia. Understanding the processes involved in the regulation of amyloid production via cholesterol is the first step towards discovering new pathways involved in Alzheimer?s disease so that new targets can be identified. If changes in lipid rafts can be influenced by drug treatment, then this work will inform the development of new drugs to treat Alzheimer?s disease. Some drugs aimed at preventing the abnormalities in amyloid are in development, however these are aimed at different pathways and until we have an effective treatment there is still a need to find new drug targets to combat Alzheimer?s disease.
Key research findings generated from researchers in the Neurodegeneration Interdisciplinary Research Group are posted on the Institute Psychiatry website. This information is accessible to all and therefore provides the lay public with information about the progress of our research. Topics of special interest are reported as press releases whenever appropriate.

Technical Summary

The deposition of amyloid beta-peptide (Abeta) in the brain is the probable trigger for neurodegeneration in Alzheimer?s disease. However, although there is evidence of rapid signal transduction changes in neurons in response to Abeta exposure, the molecular mechanisms that result in neuronal cell death remain unknown. We have shown that activation of the tyrosine kinase, fyn, occurs within minutes of application of Abeta to neurons in culture and the amount of fyn associated with lipid rafts increases in response to Abeta; neurons from fyn-/- mice are resistant to Abeta toxicity. Lipid rafts are the probable location at which Abeta triggers the neurotoxic response and this may partially explain why lowering cholesterol is protective against developing Alzheimer?s disease. We propose to apply proteomics to investigate the function of changes in abundance of lipid raft proteins and post-translation changes in these proteins in the response of neurons in culture to Abeta exposure. We shall also investigate how lowering the cholesterol content affects the susceptibility of neurons to Abeta and the corresponding protein changes by proteomics. We shall investigate by proteomics the Abeta-induced changes in lipid raft proteins in neurons from fyn-/- mice with the aim of identifying which proteins are critical to the neurotoxic response. The results of these investigations will increase knowledge of the initiating mechanisms of neurodegeneration and may lead to the identification of new therapeutic targets for Alzheimer?s disease.
 
Description BRC project grant
Amount £10,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start  
 
Description MRC strategic grant
Amount £430,008 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start  
 
Description PRT brain banking research funds/Psychiatry Research Trust
Amount £7,494 (GBP)
Organisation King's College London 
Department Psychiatry Research Trust
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description PSP project grant/Progressive supranuclear palsy association
Amount £32,200 (GBP)
Organisation Progressive Supranuclear Palsy Association (PSPA) 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description RS industry fellowship
Amount £104,610 (GBP)
Organisation The Royal Society 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description Wellcome Trust Project Grant
Amount £148,185 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Title Stacking gel method 
Description Protocol for quantitative proteomics of cellular membranes and membrane rafts 
Type Of Material Technology assay or reagent 
Year Produced 2009 
Provided To Others? Yes  
Impact Publications 
 
Title Tau antibodies 
Description Antibodies produced to tau 
Type Of Material Antibody 
Provided To Others? No  
Impact The antibodies work well against the antigen to which they were raised. their suitability in other applications will be assessed 
 
Company Name Proteome Sciences plc 
Description http://www.proteomics.com/ 
Impact Joint patents with King's College London relating to tau phosphorylation in Alzheimer's disease. Development of TMT methodology for quantitative proteomics. Biomarker assays
Website http://www.proteomics.com/products-and-services/cns/alzheimers-plasma-9-plex
 
Description Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Public Open Day on dementia and neurodegeneration, including talks and lab tours
Year(s) Of Engagement Activity Pre-2006,2006,2007,2008,2009,2010,2011,2012,2013,2014,2015,2016,2017
 
Description Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Demonstrations at MRC Centre for Neurodegeneration Research Open Day

Not known
Year(s) Of Engagement Activity 2006,2007,2008
 
Description Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Presentations to members of the public at the MRC Centre for Neurodegeneration Open Day, King's College London

Presentation of information
Year(s) Of Engagement Activity 2006,2007,2008,2010,2011
 
Description PSP Bulletin 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Regular contributions describing progress to the Progressive Supranuclear Palsy Association Bulletin

Not known
Year(s) Of Engagement Activity 2006,2007,2008
 
Description Report 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Article provided on work in my reseearch group which was published in the Institute of Psychiatry Annual Research Report

Not known
Year(s) Of Engagement Activity 2008