How does stress regulate tau-associated synaptic function?

Lead Research Organisation: University of Bristol
Department Name: Henry Wellcome LINE

Abstract

Stress is a normal daily experience, and is ordinarily a useful physiological response. However, prolonged, chronic stress can have a significant negative impact on health, and is thought to underlie and contribute to the onset of several diseases. At the cellular level, stress hormones can change neuronal function, but our understanding of the mechanisms underlying these effects is currently limited. Our overall objective is to examine how stress contributes to ageing in the brain. More specifically, we're interested in determining how dynamic communication between nerve cells can be dysregulated by stress hormones. Our project focuses on the role of a protein named tau, and how it might mediate the impairing effects of stress. Tau has well-established roles in several neurological pathologies, and our preliminary investigation has revealed a possible causal relationship between stress hormones and the aberrant regulation of tau protein in neurons. Our proposed research is of a fundamental, basic science in foundation. However, findings from our study could well improved our understanding of the molecular mechanisms underlying stress hormone-dysregulation of the central nervous system, and may shed new light on why stress might contribute to ageing.

Technical Summary

The project is designed to characterize the mechanisms relating stress with aberrant synaptic plasticity, specifically the role of stress hormone in the initiation of the synapse death signal pathway (SDP) and subsequent changes in gross spine anatomy, with a particular focus on the involvement of tau hyperphosphorylation (pTau; tauopathy). The first objective is to identify how the glucocorticoid (GC)-induced pTau in CA1 neurons in the hippocampus contributes to the impairment of synaptic plasticity. The specific phospho-residues, from a selection chosen for their relevance to synapse elimination pathways, will be mutated into phospho-dead forms of tau, and then expressed in cultured organotypic hippocampal slices. The capacity for GCs to then impair synaptic plasticity will be examined, allowing us to determine the phosphocode relevant to GC-mediated synapse ageing. We will also examine the contribution of known SDP kinases and proteases to these events, with a specific focus on the GSK-3beta signalling pathway. The second objective is to examine how the GC-induced pTau regulates the protein machinery that is responsible for AMPAR endocytosis. We will examine the role of GC-induced pTau in the regulation of the interactions between PICK1 and GluA2 AMPARs, and GRIP and GluA2 AMPARs, pivotal mechanisms in the endocytosis of AMPARs. We will then move on to examine a potential role of key tau interacting protein PACSIN in pTau-mediated AMPAR endocytosis. Finally, we will test the hypothesis that the dysregulation of synaptic plasticity by GC-induced pTau is concomitant with changes to synaptic integrity. Here we will examine dendritic morphology by assaying spine size and density using two-photon microscopy, following exposure to GCs.

Planned Impact

Academic beneficiaries: The beneficiaries from this research depend on the success of the study. At the least, our integrative approach will provide novel and fundamentally important information for a range of basic scientists who are actively pursuing research concerning stress and biological ageing. Specifically, it is yet to be fully understood how the environment affects our biological systems and leads to brain ageing. Accordingly, our proposal could make a very novel and worthy contribution to the understanding of how biological stress affects synaptic integrity and its fate between survival and death. Therefore, the academic beneficiaries include a wide-range of researchers in the science community, particularly those involved with synaptic biology and neuronal function.

Commercial beneficiaries: Since the proposed study is seeking a fundamental understanding of synapse biology, no immediate links with the commercial sector are proposed. However, there is potential for translation into enterprise. Findings from this proposed study, for instance the effect of stress on biological mechanisms of brain ageing, are to be presented during at least two international conferences. Furthermore, a high-priority is to publish work in high-impact journals. This should give the commercial sector opportunity to engage with findings generated from this work. There is a growing population of ageing-related neurodegenerative disease, and most cases are progressive diseases. Unfortunately, there is no effective therapeutic strategy for these progressive ageing-related diseases. There is slow progress in terms of R&D from the industry sector due to high-risk/lack of understanding of biological mechanisms of the ageing neuron. This work aims to identify novel mechanisms underlying synaptic function, which could have potential in the identification of new therapeutic targets for diseases related with ageing mediated progressive synaptic impairment. Thus, outcomes of this study will provide a platform for new pathways of 'academic-industry joint research environments', and facilitate therapeutic target discovery.

Public sector beneficiaries: We aim to understand how stress contributes to the ageing process. This is an issue of paramount importance in our highly-industrialised society, where the daily stress is taken as norm, yet our understanding of the long-term effects of this are primitive. Our study has the potential to reveal fundamental biological mechanisms that underpin the relationship between stress and accelerated ageing, information that could well inform both future study and therapeutic agenda. More critically, revealing a causative link between stress and the acceleration of brain pathology could well lead to a fundamental reassessment of the dangers of chronic and permissive stress, which would inevitably have an impact on a societal level. Providing better health outcomes in ageing is clearly of significant importance in a society that is experiencing, and will continue to experience for the foreseeable future, an increasing proportion of elderly persons in the population. Unfortunately, there is no effective solution to stop ageing-related progressive neuronal diseases, which in most cases require long-term care. Therefore, it impacts individual families as well as society. Public sector beneficiaries also include members of the public through public engagement events organised by the University, academic science community and media. Public events are regularly held to inform and educate the general public in research undertaken by the University. Further, students will also benefit from the research - the applicants actively participates in school visits to explain research undertaken, and often supervises students who chose to perform work experience in the laboratory. These activities are very important to keep stable and continuation of research for the long-term.
 
Description A wealth of evidence suggests that the stress hormones glucocorticoids (GCs) modulate neuronal function and can induce neurodegeneration and cognitive deficits. GCs have been shown to facilitate long-term depression (LTD) and inhibit long-term potentiation (LTP), suggestive of aberrant synapse weakening. However, the molecular mechanisms behind these effects are not fully understood. We hypothesised that glycogen synthase kinase-3 beta (GSK-3ß), known to be important in synapse weakening, would be sensitive to modulation by GCs, and this would be central to GC-induced synaptic impairment. Together these findings unveil a molecular crossover between GCs and synapse weakening signals, and indicate the potential for stress-induced priming of neurodegeneration.
Exploitation Route Potential translation to drug discovery for neurodegenerative disease
Sectors Pharmaceuticals and Medical Biotechnology

 
Description MRC-KHIDI London Health Forum 2016
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
 
Description Bilateral Programme
Amount £14,000 (GBP)
Organisation Foreign and Commonwealth Office (FCO) 
Sector Public
Country United Kingdom
Start 04/2016 
End 03/2017
 
Description Collaborative Research Grant
Amount £2,200,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2017 
End 02/2021
 
Description UK Dementia Research Institute Professorship
Amount £1,500,000 (GBP)
Organisation UK Dementia Research Institute 
Sector Academic/University
Country United Kingdom
Start 03/2018 
End 12/2023
 
Description UK-Korea Neuroscience Conference Grant 2016
Amount £5,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2016 
 
Description UK-Korea Neuroscience Symposium
Amount £20,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 08/2016 
End 07/2017
 
Description UK-Korea Partnering Award
Amount £9,800 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 05/2016 
End 04/2017
 
Description Bristol-Seoul National University Hospital research consortium 
Organisation Seoul National University Hospital
Country Korea, Republic of 
Sector Hospitals 
PI Contribution Bristol will provide novel mechanism of pathophysiology and Seoul will share their big data and new device.
Collaborator Contribution Provide patient big data and genomic data.
Impact UK-Korea Spring Health Forum with Korean government and MRC.
Start Year 2016
 
Description Protein aggregation and neurotoxicity 
Organisation University of Cambridge
Department Department of Chemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution Using different research tools, this collaboration bring together between neurophysiology and molecular imaging in living tissue
Collaborator Contribution Advanced molecular imaging tool with nano-scale resolution.
Impact We are preparing research manuscript to submit.
Start Year 2017
 
Description 10th UK-Korea Neuroscience Symposium in London (21-22 Aug. 2017) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact UK-Korea Neuroscientists presented their updated finding and discussed how to translate these for therapeutic applications in the future.
Year(s) Of Engagement Activity 2017
URL https://www.ukorea.ac.uk/10th-uk-korea-neuroscience-symposium-21st-22nd-august-2017-the-royal-societ...
 
Description 26th Neuropharmacology Conference (San Diego) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This conference discussed about the synaptic mechanisms in various brain diseases. 100 postdoctoral researchers and 100 postgraduate students were attended and more than 100 academic profession including industry.
Year(s) Of Engagement Activity 2016
 
Description 2nd Annual Neuroscience R&D Technologies Conference (London) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This conference aims at creating a platform for all the stakeholders to discuss, brainstorm and find answers to the ongoing question & challenges in the neuroscience research and recent advancements in neuroscience R & D technologies.
Year(s) Of Engagement Activity 2016
 
Description 3rd Annual Neuroscience R&D Technologies Conference, London (28-29/Sep. 2017) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact More than 100 academia and industries discussed new technology and finding for Neurodegenerative disease research.
Year(s) Of Engagement Activity 2017
URL http://www.mnmconferences.com/3rd-Annual-Neuroscience-R-D-Technologies-Conference#Speakers
 
Description 7th London Health Forum in South Korea 
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 Forum made a new UK-Korea collaboration funding program.

After Forum, medias and general public asked vision of UK-Korea collaboration of medical research in Alzheimer's disease.
Year(s) Of Engagement Activity 2015
 
Description Bristol Neuroscience Public Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Public lecture: New conceptual understanding of Alzheimer's disease
Year(s) Of Engagement Activity 2016
 
Description Hippocampus Conference in Sicily, Italy (2-6 June 2017) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Research conference at Sicily (June 2017), more than 200 neuroscientists joined and discussed their new findings.
Year(s) Of Engagement Activity 2007
URL http://hippo.euroconferences.org/program.html
 
Description IBRO-APRC Advanced School in Korea (18-27 Oct. 2017) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact The "IBRO-APRC Advanced School" provided an interactive platform for young aspiring neuroscientists (Ph.D students, post-doctoral fellows, and junior researchers) in the Asia-Pacific region to discuss and promote their understanding of brain functions including cellular mechanisms, synaptic connections, and dynamic patterns of activity.
Year(s) Of Engagement Activity 2017
URL http://www.kbri.re.kr/new/pages/sub/page.html?mc=3352
 
Description London Health Forum (Royal Society London) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact This forum aims new policy for health science and health care for ageing.
Year(s) Of Engagement Activity 2016
 
Description Society for Neuroscience (USA) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact 250 audience attended for scientific debate, "Synaptic pathophysiology of Alzheimer's disease".
Year(s) Of Engagement Activity 2016
 
Description UK-JAPAN Neuroscience Symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact 80 Neuroscientists and Japanese Medical Research Funding agent (AMED) and MRC attended for UK-JAPAN Symposium for Neurodegenerative disease. Formal research presentation and debate were scheduled over two days programme (5-6/March 2018) at the Royal Society London. AMED expressed their vision and strategy for collaboration with UK funding agent (eg, MRC) and they would like to put new policy and programme.
Year(s) Of Engagement Activity 2008
URL https://www.eventbrite.co.uk/e/uk-japan-neuroscience-symposium-tickets-41205943085
 
Description UK-Korea Future Health Forum 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Talk raised key conclusion: UK-Korea collaboration in Health and Care.

Press interview
Year(s) Of Engagement Activity 2015
 
Description UK-Korea Spring Health Forum 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact UK-Korea Spring Health Forum was funded by FCO and Korea Ministry of Health and Welfare. This forum aims for developing medical research and healthcare policy relationship in new fields of interest. Panel discussion concluded new policy for ageing and related R&D strategy.
Year(s) Of Engagement Activity 2017