Role of Wnt in the decline of oligodendrocyte generation in the ageing brain

Lead Research Organisation: University of Portsmouth
Department Name: Inst of Biomedical and Biomolecular Sc

Abstract

The massive computing power of the brain depends on the insulation of nerve cell connections with myelin sheaths, by cells known as oligodendrocytes (OLs). Bundles of these 'myelinated' connections form the white matter that is very prominent in the human cortex. Although a loss of cortical white matter and myelin has been documented in cognitive decline, the causes are unknown.

There is evidence that OLs are continuously lost and regenerated from a pool of OL progenitors (OPs). For unknown reasons, the ability of OPs to generate OLs declines with age, which underlies the loss of myelin and cognitive functions. The applicant has identified a key factor that drives OL generation in the adult brain and which is deregulated in ageing. This factor is known as Wnt (pronounced wint), and the aim of this project is to determine the mechanisms by which Wnt controls OP generation and OL/myelin loss in the ageing mouse brain. This will provide new knowledge on the mechanisms underlying myelin loss in ageing brain and may ultimately lead to the identification of new cellular targets for protecting myelin and preserving cognitive function.

This fundamental research fits the BBSRC Research Priority of 'Healthy ageing across the lifecourse'.

Technical Summary

Oligodendrocytes are specialised to form myelin in the CNS. Myelin is essential for rapid neuronal connectivity that underlies the massive computing power of the human brain. Studies in humans have shown loss of myelin and white matter shrinkage after the age of 50 is associated with decline of higher cognitive functions. Fate-mapping studies in mice provide direct evidence that this is normally replaced by oligodendrocytes newly generated from endogenous oligodendrocyte precursors (OPs). However, for unknown reasons there is a decrease in the regenerative capacity of OPs in the ageing brain. The mechanisms regulating oligodendrogliogenesis in the adult and aging brain are unresolved. However, the applicant provides several new lines of evidence of a fundamental role for deregulation of Wnt signalling. In recent studies, the applicant has identified a major role for Wnt in driving oligodendrogliogenesis and myelination in vivo in the mouse brain (Azim et al., 2014a,b). Now, in pilot studies on the optic nerve, an archetypal CNS white matter tract, we show that Wnt signalling continues to drive oligodendrogliogenesis in the mature adult nerve but not in old-age (18 months, equivalent to age 60 in humans). Furthermore, we show that multiple elements of Wnt signalling that control oligodendrocyte generation are severely altered in ageing white matter. To take this work forward, the applicant has developed a Cre/LoxP mouse line that targets Wnt signalling in OPs. These mice provide a major new advance that will enable the applicant to achieve the aims of this project and test the hypothesis that deregulation of Wnt signalling underlies the decreased regenerative capacity of OPs in the ageing brain. The planned epxeriments will generate new fundamental knowledge on the functions of Wnt in oligodendrocyte cell biology and mechanisms of cognitive decline in the ageing brain.

Planned Impact

The main beneficiaries of the research will be other scientists, and dissemination of research findings will be through the normal routes of publications, reviews and presentations at meetings. In the longer term, this research is also likely to be of interest to clinicians, patient groups, and the wider public. We will publicise the support we receive for this project and explain the research through public forums. Where possible, we will make ourselves available to speak to local and national media on the importance of this research to the public and how grant support drives this much needed fundamental research.
It is not anticipated that any directly patentable data will arise from this project, but the longer term plan is to use the information gained in this research to identify new potential therapeutic targets for promoting a healthy brain in ageing and across the lifecourse. This would have considerable wider impact. We will use several routes to communicate this to potential user groups and the general public. We will present live demonstrations to local schools and the public, and write articles for specialised magazines for patients who may benefit from the findings of this research project. In addition, this project is directly relevant to ageing research and as a member of the University of Portsmouth Ageing Network (UPAN) and Alzheimer's Research UK (ARUK) Southern Network co-ordinated out of Southampton University, the applicant will have a direct route to communicate this research to potential end-users and interst groups.
 
Description We have: (1) developed a new transgenic mouse strain; (2) discovered new cellular and molecular targets in the ageing brain; and (3) identified potential drugs to protect ageing white matter. These data have been presented at a number of conferences, to the public in lectures and lab visits, and in parliament. A number of full papers have been published. In addition, we have patented some of the findings and set up a spin-out company to pursue these findings.
Exploitation Route We have identified a series of small molecules that have the capacity to protect ageing white matter. This led to a patent and a spin-out company to pursue these findings.
Sectors Pharmaceuticals and Medical Biotechnology

 
Description With our collaborators in INSERM Lyons, we have filed a patent as inventors. This led to the formation of a spin-out company GliaGenesis.
First Year Of Impact 2017
Sector Pharmaceuticals and Medical Biotechnology
 
Title PHARMACEUTICAL COMPOSITIONS FOR USE IN THE TREATMENT OF BRAIN INJURIES OR DEMYELINATING DISORDERS 
Description The invention is in the field of neuroregenerative medicine. Controlling the fate of neural stem cells represent a key therapeutic strategy in neuroregenerative medicine. The inventors used in silico genomic approaches, namely searchable platform-independent expression database/connectivity map (SPIED/CMAP) strategy, to identify small molecules that are predicted to regulate transcriptional changes associated with oligodendrogenesis and/or neurogenesis in the subventricular zone (SVZ) neurogenic niche. The approach was validated by demonstrating that two of the identified small molecules, inhibiting PI3K/Akt and GSK3? respectively, were able to differentially direct the fate of NSCs in vivo, to promote oligodendrogenesis and neurogenesis, in the postnatal and adult SVZ. The present invention thus relates to compounds, such as PI3K or GSK3? inhibitors, and pharmaceutical composition for use in the treatment of brain injuries, such as perinatal hypoxia/ischemia, or demyelinating disorders, such as periventricular leukomalacias or multiple sclerosis. 
IP Reference WO2018178194 
Protection Patent application published
Year Protection Granted 2017
Licensed No
Impact None to date
 
Company Name GliaGenesis 
Description Normal brain ageing is also associated with a significant loss of glial cells and white matter within the brain after people reach approximately 50 years of age. Glia are essential for neuronal function, survival and integrity. Alzheimer's, Parkinson's and Motor Neuron Diseases (ALS) as well as Multiple Sclerosis are all neurodegenerative diseases in which glial cell loss is now known to play a fundamental role in their neuropathology. Our aim is to provide greater insight into how glial cells aid and support neurons and find new therapeutics that can selectively promote survival of existing glial cells and prompt their regeneration. 
Year Established 2017 
Impact None to date
Website http://www.gliagenesis.com/
 
Description 2016 Science Together: Science Postgraduate Research Conference (UoP) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact The Research Student, Ashik Kalam, presented his spinal cord injury data to a general science audience. He was congratulated on his presentation and it parked new interest in the field.
Year(s) Of Engagement Activity 2016
 
Description Christine Rose research exchange 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact New collaborator fr9om Christine Rose group invited to my lab to exchange technical expertise
Year(s) Of Engagement Activity 2016
 
Description Fishbourne CE promary school talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Talk to primary school children on brain research
Year(s) Of Engagement Activity 2016
 
Description Glial meeting in Salvador Brazil 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The PDRA Dr Andrea Rivera was invited to present our data at a Glial meeting in Salvador Brazil, which sparked questions and lively discussions, leading to collaborations.
Year(s) Of Engagement Activity 2017
 
Description Italy, Aqua Therme May 2017 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Public meeting on brain health during ageing, resulting in lively discussions and the plan to organise a larger meeting in 2018.
Year(s) Of Engagement Activity 2017
 
Description Lab Tour 
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 The PI provided a guided tour of his labs and an overview of the research. The audience were very excited about the research.
Year(s) Of Engagement Activity 2016
 
Description Lab Visits for Ageing 
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 30 people visited my labs as part of the ageing recognition outreach activities
Year(s) Of Engagement Activity 2016
 
Description Living with Dementia 2017 
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 meeting in which we presented a science café on our research
Year(s) Of Engagement Activity 2016
 
Description Living with Dementia, Southampton UK Jan 2016 
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 A mixed audience of PPI, academics, clinicians and funders, with the purpose of promoting understanding and bilateral communication. Considerable interest amongst PPI.
Year(s) Of Engagement Activity 2016
 
Description Living with MS 18th of November, Southampton 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Living with MS 18th of November, Southampton - stand organiser and oral presentation, sparked questions and lively discussions.
Year(s) Of Engagement Activity 2017
 
Description Lyons neural stem cell group meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Meeting with Olivier Raineteau and Kasum Azim on taking our research forward in an open and collaborative way
Year(s) Of Engagement Activity 2016
 
Description MS Society visit 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact Visit to my labs from MS Society to discuss research
Year(s) Of Engagement Activity 2016
 
Description MS patients and supporters lab visit 
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 Patients, carers and/or patient groups
Results and Impact The local MS group came to visit our labs
Year(s) Of Engagement Activity 2016
 
Description Milan University Dec 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Presentation to potential research collaborators, which sparked a new collaboration.
Year(s) Of Engagement Activity 2017
 
Description PDRA Dr Andrea Rivera Joined BBSRC Skills and Career Postdoctoral advisory Group October 2017 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Joined BBSRC Skills and Career Postdoctoral advisory Group October 2017
Year(s) Of Engagement Activity 2017
 
Description Pint of Science Talk 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Presentation at the Pint of Science in Portsmouth
Year(s) Of Engagement Activity 2016
 
Description Pint of Science, Portsmouth 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact The PI, Professor Arthur Butt, presented a talk on the brain as part of the Pint of Science week. There was considerable feedback and interest from the audience.
Year(s) Of Engagement Activity 2016
 
Description Public Talk - inaugral 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Public Lecture on research in my group
Year(s) Of Engagement Activity 2016
 
Description Public Talk, Connelli, Italy 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Public Talk in Connelli, Italy, on our work focusing on maintaining a healthy brain across the lifecourse. Over 100 people attended the talk, ranging from general public to local and national politicians and media.
Year(s) Of Engagement Activity 2018
 
Description Stem4Britain presentation at the House of Parliament 12/03/2018 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Stem4Britain presentation at the House of Parliament 12/03/2018, sparked questions and discussions with MPs and others
Year(s) Of Engagement Activity 2018
 
Description Talk to local MS group 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Patients, carers and/or patient groups
Results and Impact Presented MS research to the local MS group
Year(s) Of Engagement Activity 2016
 
Description Turin University and Medical School, Dec 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Talks with potential collaborators that sparked discussions and potential for collaborative research.
Year(s) Of Engagement Activity 2017
 
Description Visit Christine Rose Germany 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Talk with Christine Rose group and exchange of ideas and arrange future lab visits
Year(s) Of Engagement Activity 2016
 
Description Visit lab in Lyons, INSERM 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The PI visited the lab of Olivier Raineteau in Lyons for a workshop to exchange research ideas. This led to new collaborations.
Year(s) Of Engagement Activity 2016
 
Description Visits by Silvia Lima Costa and Suzanna Braga July-Aug 2017 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Brazilian colleagues visited my labs and we held a workshop for the exchange of ideas, resulting in lively discussions and future collaborations.
Year(s) Of Engagement Activity 2017
 
Description iBrain Lecture University of Dusseldorf 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Presentation of new data on brain ageing and pharmaceutical interventions, which sparked questions and discussions afterwards.
Year(s) Of Engagement Activity 2017