Alzheimers and prion diseases: cellular and genetic mechanisms of neurodegeneration

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

Abstract

Alzheimers disease is the commonest form of dementia that affects a large proportion of the elderly population of the UK. Many other people are affected through knowing a family member or friend who has this debilitating disease. Prion diseases, such as Creutzfeldt-Jakob disease (CJD), are much rarer but have received much attention in recent years because of the still unknown number of people in the UK infected following the epidemic of bovine spongiform encephalopathy (BSE) (mad cow disease). Both these brain diseases are fatal and, as yet, there are no cures for either disease. We have noticed similarities in the way that brain cells regulate the processing of key proteins that cause Alzheimers and prion diseases. The aim of this proposal is to investigate these processes in cells and animals, as well as in post-mortem brain tissue from Alzheimers patients. The results from our work will help us understand how these diseases develop and may aid in the identification of new treatments.

Technical Summary

Alzheimers disease (AD) is the major neurodegenerative disease of the aging brain that is extremely complex and poorly understood but which poses an ever-expanding burden on the Health Service and society in an aging population. By contrast the prion diseases, such as Creutzfeldt-Jakob disease, 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. Our working hypothesis is that common molecular and cellular mechanistic features exist between AD and prion diseases. AD is characterised by the deposition in the brain of amyloid-beta peptides that are derived by proteolytic cleavage of the amyloid precursor protein (APP), while prion diseases are characterised by the conformational conversion of the cellular form of the prion protein (PrPC) to the pathogenic form, PrPSc. The overall aim of this proposal is to elucidate further and compare the cellular and genetic regulation of the proteolytic mechanisms and protein-protein interactions that are involved in the normal and pathogenic processing and functions of APP and PrPC. The specific objectives are:
(a) to determine the cellular mechanism by which PrPC inhibits the rate limiting cleavage of APP by the beta-secretase BACE1, and by what mechanism other interacting proteins (that we have identified from the BACE1 and APP interactomes) modulate the cleavage of APP. In addition, we will examine whether key BACE1 and APP interacting proteins are altered in AD and aging, establish if PrPC modulates the gamma-secretase cleavage of APP and determine the mechanism by which the modulation of neurotransmitter receptor signalling increases the alpha-secretase cleavage of APP;
(b) to determine the roles of PrPC endoproteolysis and interacting proteins (some of which are shared with APP) on PrPC function and conversion to PrPSc, and whether PrPC protects against cognitive dysfunction in a mouse model of AD. In addition, we will assess whether localisation of PrPC in different membrane domains modulates its protein interactome;
(c) to investigate the mechanism by which the intracellular domain of APP and histone deacetylase inhibitors may regulate expression of a subset of AD-related genes, especially neprilysin, and to examine if there are global changes in neuronal chromatin in AD and prion disease.
Appreciating the intricacy of the cellular systems will not only advance our understanding of these neurodegenerative disorders but will also help with designing therapeutic interventions as precisely as possible to avoid unintended consequences.

Publications

10 25 50
 
Description MRC Dementia stratification workshop
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description TSB dementia stratification (London)
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description A cell surface, lipid raft-based signaling complex links amyloid-? to tau via Fyn'
Amount £327,074 (GBP)
Funding ID ARUK-PG2013-12 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2013 
End 09/2016
 
Description Differential production of amyloid-beta from the APP isoforms
Amount £86,000 (GBP)
Funding ID ARUK-PhD2012-5 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2012 
End 09/2015
 
Description Investigating the neurotoxic mechanisms of amyloid-? oligomers: role of the prion protein
Amount £244,926 (GBP)
Funding ID ART-PG2010-2 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2010 
End 09/2013
 
Title PrP null - I5 mice 
Description Crossing of PrP null mice with I5 mice wild type for human APP 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact
 
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-Bristol 
Organisation North Bristol NHS Trust
Country United Kingdom 
Sector Public 
PI Contribution My research team has provided experimental data
Collaborator Contribution Colleagues in Bristol have supplied human brain material and associated data
Impact Outputs listed elsewhere
Start Year 2011
 
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 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 Alumni (Leeds) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Supporters
Results and Impact Several alumni attended of which some have decided to donate funds for our research

Funding to support summer placement students and a PhD student secured
Year(s) Of Engagement Activity 2012,2013
 
Description BBC Breakfast TV 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact .
Year(s) Of Engagement Activity 2014,2015
 
Description Dementia website 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact .
Year(s) Of Engagement Activity 2014
URL http://www.fbs.leeds.ac.uk/blogs/dementia/
 
Description MRC Cell Biology or Neurons and Glia - dinner discussion 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Discussion paper produced by MRC

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Year(s) Of Engagement Activity 2015
 
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 Parliament (London) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Approx 25 members of parliament and public attended, sparked questions.

Too ealry to tell
Year(s) Of Engagement Activity 2013
 
Description Public lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact 50 members of the public/health profession attended

.
Year(s) Of Engagement Activity 2011
 
Description Radio interviews (2013) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Invited to talk about research on BBC Radio Leeds, BBC Radio 4 Today programme, radio programme for Ireland.

Increased awareness of our research on dementia
Year(s) Of Engagement Activity 2013
 
Description School visit, Huddersfield 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Schools
Results and Impact 30 pupils attended

.
Year(s) Of Engagement Activity 2012
 
Description school visit, Huddersfield 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact 20 sixth form students attended

.
Year(s) Of Engagement Activity 2011