Non-cell autonomous mechanisms of synapse pathology

Lead Research Organisation: University of Edinburgh

Abstract

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Technical Summary

The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019.

Neuropathologically, synapse loss correlates most strongly with the progressive cognitive decline in Alzheimer’s disease (AD). While a central role for synapses in AD pathogenesis and in the spread of pathological proteins through the brain is now well-accepted(1), we are only beginning to understand the implications of non-neuronal cells in these processes. Spires-Jones’ DRI programme is focused on the contributions of nonneuronal cell types to synapse degeneration. A large part of this work focuses on Apolipoprotein E e4 (APOE4) which may be a crucial link between synapse degeneration, inflammation, and the wider NVGU. Students in the Spires-Jones lab have recently completed a systematic search and comprehensive review of the literature relating APOE to neurodegeneration, inflammation, and/or the spread of pathological proteins through the brain (2). The review of the 108 papers that matched our inclusion criteria shows strong evidence in the field implicating APOE4 in synapse degeneration(3, 4), neurodegeneration(5, 6), and inflammation(7-11) (examples of only a few key papers cited here). The systematic literature search also revealed key gaps in our knowledge, which we plan to address in this DRI programme. In particular, we will investigate the molecular pathways in synapses influenced by APOE genotype in human AD brain and how these affect synaptic function in mice in vivo and in human iPSC derived neuron/glia co-cultures.

In addition to synapse loss influencing cognitive decline, synapses have recently emerged as the conduit for the spread of tau through the brain. In our systematic literature search, there were no data directly implicating APOE in the spread of tau through synapses, however indirect evidence from papers showing a role for APOE in synapse loss and inflammation indicate that this remains an unexplored possibility. ApoE has a role in presynaptic vesicle release, which could impact the release of tau from synapses (12). Glia may be important for this process as microglia and astrocytic end feet have the potential to clear tau as it spreads from pre to postsynaptic terminals. APOE4 has also been associated with faster cognitive decline in Aß+ non-demented individuals(13), which could be due to more rapid tau spread. There are some data indicating that APOE4 is associated with higher levels of pathological tau in CSF and brain(14, 15), but to our knowledge, the hypothesis that apoE influences tau spread has not been formally tested. This forms another key part of the DRI programme.

Publications

10 25 50
 
Description 'Tackling gaps in developing life-changing treatments for dementia' workshop
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a national consultation
 
Description Authorship of a policy briefing note for Scottish Government - Open Research
Geographic Reach National 
Policy Influence Type Implementation circular/rapid advice/letter to e.g. Ministry of Health
URL https://www.scottishscience.org.uk/sites/default/files/article-attachments/SSAC%20Briefing%20Note%20...
 
Description Brain Communications Funding
Amount £175,000 (GBP)
Organisation Guarantors of Brain 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2019 
End 04/2026
 
Description Investigating a novel target for modulating synapse degeneration in Alzheimer's disease - in vivo target validation in mice.
Amount £144,000 (GBP)
Organisation Autifony Therapeutics 
Sector Private
Country United Kingdom
Start 10/2019 
End 09/2020
 
Description Network of Centres of Excellence in Neurodegeneration (COEN)
Amount £310,000 (GBP)
Funding ID CoEN2020/3 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 08/2020 
End 04/2022
 
Description Target Validation Pathfinder Grant
Amount £49,780 (GBP)
Funding ID ARUK-TVPG2018-010 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2019 
End 07/2020
 
Description Alberto Lleo, Barcelona 
Organisation Hospital de Sant Pau
Country Spain 
Sector Hospitals 
PI Contribution We train students and staff in array tomography technique and share specially embedded tissue.
Collaborator Contribution Super resolution imaging of array tomography and sharing embedded tissue.
Impact • 4 papers • 1 CoEN grant
Start Year 2013
 
Description Alector 
Organisation Alector
Country United States 
Sector Private 
PI Contribution We are using Alector's proprietary reagents to study mechanisms synapse phagocytosis by microglia.
Collaborator Contribution The partner provides proprietary reagents
Impact nine
Start Year 2019
 
Description Annexon 
Organisation Annexon Biosciences
Country United States 
Sector Private 
PI Contribution We are using proprietary reagents from the partner to study mechanisms of synapse phagocytosis by microglia
Collaborator Contribution The partner provides proprietary reagents
Impact none
Start Year 2019
 
Description Autifony collaboration 
Organisation Autifony Therapeutics
Country United Kingdom 
Sector Private 
PI Contribution We have tested a therapeutic pathway of interest to the company in our mouse models of Alzheimer's disease and looked for evidence in human tissue.
Collaborator Contribution The partners helped design experiments and provided reagents and advice on analyses
Impact - none yet
Start Year 2018
 
Description Collaboration with Patrik Verstreken to study synaptic tau 
Organisation Flanders Institute for Biotechnology
Country Belgium 
Sector Charity/Non Profit 
PI Contribution We are collaborating with Patrik Verstreken's lab to study synaptic tau. We provide data and samples of human brain tissue via our ethically approved brain bank for their work.
Collaborator Contribution Patrik's group are providing novel fly lines for our work.
Impact We have so far published a Nature Communications and Neuron paper together.
Start Year 2017
 
Description Collaborative grants from pharmaceutical company 
Organisation AbbVie Inc
Country United States 
Sector Private 
PI Contribution We are studying synaptic resilience in a well-characterised cohort using cutting-edge methods.
Collaborator Contribution partner provides funding for collaborative research, input on data analysis, and thoughts of useful therapeutic avenues.
Impact - data sets have been generated but not yet published
Start Year 2018
 
Description FNIH collaboration biomarkers 
Organisation Foundation for the National Institutes of Health (FNIH)
Country United States 
Sector Charity/Non Profit 
PI Contribution I am one of 3 lead PIs on a large collaborative grant to understand biological underpinnings of a promising synaptic imaging biomarker
Collaborator Contribution parntners provide funding and collaborators will recruit human subjects and provide tissue
Impact none yet
Start Year 2020
 
Description UCL DRI Zetterberg, Hong, 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution We provide samples of human synapses, blood, and CSF for analyses by UCL collaborators
Collaborator Contribution Zetterberg detects biomarkers in our samples and provides data Hong will study lipidomics and microglia with our samples
Impact 1 Collaborative grant from FNIH for a total of over $5 million. Pilot data and collaboration on another grant submitted.
Start Year 2018
 
Title Array tomography image analysis software 
Description We share our array tomography image analysis software, generated in MATLAB, on GitHub for anyone to use freely. 
Type Of Technology Software 
Year Produced 2019 
Open Source License? Yes  
Impact So far this has been used in house and generated a collaboration with a physicist/programmer to improve the speed by migrating to Python. 
 
Description "Dance for your life" Public engagement event with Strictly come dancing TV star Russell Grant 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact This 'Dance For Your Life' is an event full of music, dance, and learning. Participants learn from Prof Tara Spires-Jones how exercise reduces the risk of dementia then put this into practice in the 'Day in the Life of a Strictly Celebrity'workshop with Strictly Come Dancing Celebrity Russell Grant.  Followed by a reception with drinks and snacks. With special performances by University of Edinburgh Danns Ed and the Dunbar Highland Dancers.

The event was covered in the Edinburgh evening news.
Year(s) Of Engagement Activity 2019
URL https://www.eventbrite.co.uk/e/dance-for-your-life-tickets-55932637023
 
Description "Dementia Buddies" scheme 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact "Dementia Buddies" scheme lab host - people with dementia and their carers attend lab meetings to discuss science and exchange ideas. This is organised by Dr Chris Henstridge in the UK Dementia Research Institute. My lab is one of the hosting groups.

https://www.bbc.co.uk/news/av/uk-scotland-46705885/edinburgh-university-scientists-dementia-buddy-scheme
Year(s) Of Engagement Activity 2018,2019
 
Description BBC Radio 4 The World Tonight Programme interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact I was asked to comment on a neuroscience paper published in Nature which showed that perfusing dead pig brains with artificial blood could delay brain cell death. We discussed the science and future ethical implications of the study.
Year(s) Of Engagement Activity 2019
 
Description BBC Radio 4 Today Programme interview 
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 The BBC Today Programme asked for my opinion on a new scientific study out of Columbia University.
Year(s) Of Engagement Activity 2018
 
Description Coverage of Cell Reports paper in the media 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact We issued a press release about our Cell Reports paper, which was picked up by news outlets. One example was a story in the Daily Mail that was shared over 3500 times.
Year(s) Of Engagement Activity 2019
URL https://www.dailymail.co.uk/health/article-7776925/Alzheimers-hope-scientists-way-reverse-symptoms-d...
 
Description Edinburgh International Science Festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact In our Edinburgh International Science festival event "What does the future hold for dementia" sponsored by Alzheimer's Research UK, we presented the state of the art of dementia research today and what people can do to change the future predictions for rising numbers of people living with dementia. MP Joanna Cherry attended the event and has discussions with us afterwards about how policy makers can best support dementia research.
Year(s) Of Engagement Activity 2018
URL https://www.ed.ac.uk/news/2018/research-inspires-science-festival-events
 
Description Understanding Dementia - Media Planet 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact I contributed an article explaining our research findings for the general public to the Understanding Dementia campaign by Media Planet. This was distributed both online and in print via New Scientist magazine.
Year(s) Of Engagement Activity 2020
URL https://bit.ly/2YduTpz
 
Description Video Journal of Dementia Interviews 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Video Journal of Dementia interviewed me about our research in Alzheimer's disease and a new journal that I Edit.
Year(s) Of Engagement Activity 2018,2019
URL https://vjdementia.com/speaker/tara-spires-jones/