Mechanisms underlying the differential response to rosiglitazone of individuals with different ApoE genotypes

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

Abstract

Alzheimer?s disease (AD) is a very complex disorder for which there are few known risk factors. However it is known that advancing age increases the risk of developing AD as does possession of a particular type of a protein called apolipoprotein E (ApoE). ApoE occurs in three types (ApoE2, ApoE3, ApoE4) and possession of ApoE4 is associated with an increased risk of developing AD.

One of the primary characteristic features of AD is the presence in the brain of clumps of a protein called amyloid beta-peptide (Abeta), the presence of which is thought to be detrimental to nerve cells. Abeta derives from a larger protein, called amyloid precursor protein (APP), from which Abeta is cut out. Cleavage of APP occurs primarily in the membranes of nerve cells, but in specific regions called ?lipid rafts? from where it is then exported to the outside of the cell to form the detrimental clumps containing Abeta.

A drug that is used to treat diabetes (Avandia?), developed by GlaxoSmithKline, has recently been found to be useful for treating some people with AD. However, Avandia? was only beneficial for people carrying ApoE3 or ApoE2 and not ApoE4. The main functions of ApoE are to bind lipids and cholesterol and to transport them around the body. The different types of ApoE perform these functions with differing abilities but it is not known how this might relate to the differences in the observed therapeutic effects of Avandia? in AD sufferers. It is important therefore to try to understand how Avandia? is working so that better drugs can be developed.

Our hypothesis is that the differential effects of Avandia? in AD patients may be related to differences in the ApoE forms that result in different (1) ability to remove Abeta from the brain or (2) sensitivity of nerve cells to the toxic effects of Abeta.

Results that are of interest to the general public will be publicised on the MRC Centre for Neurodegeneration website and through reports in the associated bulletins as well as through press reports where appropriate.

Technical Summary

A recent study of the effects of rosiglitazone (Avandia?), a thiazolidinedione (TZD) anti-diabetic drug, in people with Alzheimer?s disease (AD) has revealed differential effects that are dependent on the apolipoprotein E (ApoE) status of individuals. ApoE4 genotype is associated with increased risk of developing AD but non-ApoE4 carriers responded positively to rosiglitazone, whereas patients harbouring ApoE4 alleles did not show improvement in symptoms.

The aim of this study is to investigate the mechanism of action of rosiglitazone and the relationship to generation of neurotoxic amyloid-beta peptide (Abeta) in different ApoE backgrounds. These experiments will investigate whether (1) rosiglitazone modifies the protein composition of lipoproteins differentially according to ApoE genotype ? this would then lead to modulation of Abeta toxicity and/or (2) Abeta generation also exhibits ApoE isoform-specific differences that are further amplified by rosiglitazone.

The proposed research plan will use astrocytic cultures expressing different ApoE isoforms to explore the possibility that ApoE influences the protein composition of ApoE-containing lipoprotein particles. In parallel studies we will examine the effects of rosiglitazone on the generation of neurotoxic Abeta, the major component of amyloid plaques in AD brain, in the lipid rafts of neurons with differing ApoE genotypes. ApoE could thus function as a regulator of protein composition, and hence function, of lipid rafts and this may account for the observed differential, ApoE genotype-dependent, susceptibility to AD based on differences in Abeta production.

The results of this study should result in identification of novel targets for AD and development of new TZDs for which patient response is not ApoE isoform selective.

Publications

10 25 50
 
Description Dementia Research Portal Working Group
Geographic Reach National 
Policy Influence Type Membership of a guidance committee
 
Description NIHR workshop on dementia research
Geographic Reach National 
Policy Influence Type Participation in a national consultation
 
Description BBSRC CASE AstraZeneca Studentship
Amount £100,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2013 
End 09/2017
 
Description BBSRC/Lilly CASE Studentship
Amount £103,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 01/2013 
End 12/2016
 
Description King's Overseas Research Studentship
Amount £98,000 (GBP)
Organisation King's College London 
Sector Academic/University
Country United Kingdom
Start 01/2013 
End 12/2015
 
Title Astrocyte secreted lipoproteins 
Description Identification of lipoproteins secreted by astrocytes 
Type Of Material Biological samples 
Provided To Others? No  
Impact N/A 
 
Description GSK 
Organisation GlaxoSmithKline (GSK)
Department Neurology and GI Centre of Excellence for Drug Discovery (CEDD) GSK
Country United Kingdom 
Sector Private 
PI Contribution Methodology to generate astrocyte cultures, obtain medium and enrich for apolipoproteins. Mass spectrometric analysis
Collaborator Contribution GSK contributed transgenic animals and relevant expertise at the outset of the project
Impact Multidisciplinary collaboration (cell biology, animal models, molecular biology, biochemistry, mass spectrometry)
Start Year 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 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 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? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Tours of the facilities and subsequent discussions with members of the public

Local interest is high
Year(s) Of Engagement Activity 2012
 
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 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 Description of ongoing laboratory research

None known
Year(s) Of Engagement Activity 2011
 
Description Year 12 mock interviews 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Year 12 school students underwent formal mock interviews

School reports that this is very useful for students preparing for university and for taking up employment after leaving school
Year(s) Of Engagement Activity 2011,2012,2013,2014,2015,2016