Amyloid precursor protein and prion protein: cellular functions, processing and roles in neurodegeneration

Lead Research Organisation: University of Leeds
Department Name: Inst of Molecular & Cellular Biology

Abstract

Alzheimer’s disease is a debilitating disorder that affects a high proportion of the elderly population of this country. Individuals with Alzheimer’s suffer from memory loss, disorientation and impairment of judgement and reasoning. Transmissible spongiform encephalopathies (TSEs) or prion diseases, such as Creutzfeldt-Jakob disease (CJD), are relatively rare but have received much attention in recent years because of the potential number of individuals in the UK affected following the epidemic of bovine spongiform encephalopathy (BSE). A major issue of current concern is that blood donors may be subclinically infected with the BSE agent and could potentially transmit variant CJD via blood transfusion to healthy individuals. The primary aim of our work is to provide more information on the two key proteins, Alzheimer’s amyloid precursor protein and prion protein, that are implicated in these diseases. Through a molecular and cell biological approach our work will provide information on the normal cellular roles of these proteins, the way in which they are normally processed, and what goes wrong to these processes in the disease situation. The results from our work may aid in the identification of novel therapeutic targets which could subsequently be exploited as potential treatments for these diseases.

Technical Summary

Alzheimers disease (AD) is the major neurodegenerative disease of the ageing brain that is extremely complex and ill understood but which poses an ever-expanding burden on the Health Service in an ageing population. In contrast, transmissible spongiform encephalopathies (TSEs), such as Creutzfeldt-Jakob disease (CJD), are relatively rare but have received much attention in recent years because of the potential number of individuals in the UK affected following the epidemic of bovine spongiform encephalopathy (BSE). AD is characterised by the deposition in the brain of senile plaques consisting predominantly of the amyloid-beta (Abeta) peptide that is derived by proteolytic cleavage of the amyloid precursor protein (APP). TSEs are characterised by the conformational conversion of the normal cellular form of the prion protein, PrPC, to a pathogenic form PrPSc. In addition to APP and PrP being critically involved in neurodegenerative disorders, there are strong similarities between the proteolytic processing, cellular location and function of the two proteins, as well as neuropathological evidence indicating an association between AD and prion diseases. The overall aim of this proposal is to elucidate further both the normal and pathological roles of PrP, APP and their metabolic products. The specific objectives are: (a) to evaluate the effect of AD therapeutic compounds on the expression and activity of the alpha-secretases that cleave APP and prevent the formation of Abeta; (b) to investigate the role of different lipid rafts in the isoform distribution and amyloidogenic processing of APP; (c) to identify the PrP lipid raft targeting molecule and evaluate its role in PrP metabolism; (d) to investigate the cellular and molecular interaction between PrP and the beta-secretase cleavage of APP; (e) to evaluate the role of proteolytic processing in the metabolism of PrPC and its conversion to PrPSc; (f) to investigate the role and regulation of Abeta catabolising peptidases in the pathogenesis of AD; (g) to evaluate the role of APP isoforms in the cellular response to oxidative stress; and (h) to identify extracellular ligands and/or receptors for APP. The results from this inter-related programme of work will not only provide novel information on the normal and pathogenic roles of APP and PrP, but may also identify new therapeutic targets and common mechanisms for AD and TSEs.

Publications

10 25 50

publication icon
Cordy JM (2006) The involvement of lipid rafts in Alzheimer's disease. in Molecular membrane biology

publication icon
Fisk L (2006) Regulation of endothelin-converting enzyme-1 expression in human neuroblastoma cells. in Experimental biology and medicine (Maywood, N.J.)

publication icon
Griffiths HH (2008) Emerging and potential therapies for Alzheimer's disease. in Expert opinion on therapeutic targets

 
Description ART Project Grant
Amount £180,000 (GBP)
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2009 
End 12/2011
 
Description MRC Programme Grant
Amount £1,200,000 (GBP)
Funding ID G0802189 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 11/2009 
End 10/2014
 
Title PrP null - J20 mice 
Description PrP null mice have been crossed with the J20 mouse model of Alzheimer's disease 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact A publication describing the effect of deletion of PrP on APP processing. 
 
Title PrP null J20 mice 
Description PrP null mice have been crossed with the J20 Alzheimer's model mouse. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact A publication reporting the results of depletion of PrP on APP processing. 
 
Title Transfected cell lines 
Description Cell lines transfected with various constructs of the prion protein or amyloid precursor protein. 
Type Of Material Cell line 
Year Produced 2007 
Provided To Others? Yes  
Impact Various publications resulting from use of cells 
 
Title Transfected cell lines 
Description Various mammalian cell lines transfected with constructs of APP, PrP and other proteins involved in Alzheimer's disease. 
Type Of Material Cell line 
Year Produced 2008 
Provided To Others? Yes  
Impact These cell lines have contributed significantly to publications arising from our research group and that of others. 
 
Description Leeds-Edinburgh 
Organisation University of Edinburgh
Department The Roslin Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual input into the design of experiments and analysis of results based on work originating from Leeds.
Collaborator Contribution Expertise in animal models
Impact Pilot grant from the Alzheimer's Research Trust and a submitted publication. Publication in PLOS ONE
Start Year 2007
 
Description Leeds-Edinburgh 
Organisation University of Edinburgh
Department The Roslin Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Ongoing intellectual input to the design of experiments and writing of grant applications based on findings arising from research in Leeds
Collaborator Contribution Initial data has been generated which is the subject of a submitted publication.
Impact Pilot grant awarded by the Alzheimer's Research Trust to establish a new mouse model for Alzheimer's disease
Start Year 2007
 
Description Media (as a channel to the public) 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Press releases issues by University, ARUK or MRC which was taken up by numerous agencies.

Increased awareness of and impact of our research. Invitations to speak on local and national radio.
Year(s) Of Engagement Activity 2007,2008,2009,2010,2011
 
Description Media - glypican 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Press release issued by University that was taken up by several agencies.

No subsequent impact
Year(s) Of Engagement Activity 2009
 
Description Mount School York 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Talk to pupils about Alzheimer's disease and our ongoing research.

No subsequent impact
Year(s) Of Engagement Activity 2009