Contribution of Wnt signalling to Amyloid Beta-mediated synaptic dysfunction

Lead Research Organisation: University College London
Department Name: Cell and Developmental Biology

Abstract

Alzheimer's Disease (AD) is a condition initially characterized by the loss of new memories, but progresses into dementia at later stages. This devastating condition afflicts people of different races, social and educational backgrounds. AD contributes to more than 64% cases of all dementias. Importantly, the number of cases of dementia will double in the next 20 years and will triple by 2050. It was estimated that in 2010, the worldwide cost of dementia represents more than 1% of global GDP. Despite extensive research, effective treatment for AD is not yet available. Thus, AD represents a real burden and challenge to our society.

AD is a progressive neurodegenerative condition that leads to the loss of nerve cells (neurons) in the brain. A cellular characteristic of AD is the progressive deposition of Amyloid-Beta (AB) protein, the main component of Amyloid plaques in AD brain. Many studies have demonstrated that AB is highly pathogenic as induces the death of neurons. For many years, scientists have focused their work in understanding how AB induces neuronal degeneration. However, the levels of AB plaques are not fully correlated with cognitive decline. In contrast, cognitive and memory deficits are better correlated with the loss of synapses, which are specialized junctions between neurons, essential for brain function. Studies in cultured neurons as well as in animal models of AD showed that AB affects the stability and function of synapses before neuronal death is evident. However, the molecular mechanisms by which AB induces these synaptic changes are poorly understood. Studying the molecules that regulate and promote the stability of synapses could provide important insights into the mechanisms by which pathogenic molecules like AB affects synapses in the adult brain.

We discovered that molecules called Wnts promote the formation, growth and maintenance of synapses in the vertebrate brain. Recently, we found that a secreted protein that blocks the function of Wnts induces synaptic loss. Importantly, this factor is elevated in brain of AD patients and in neurons exposed to AB. These results suggest that AB induces the production of this Wnt antagonist, which then promotes the loss of synapses. Consistent with this hypothesis we found that blockade of the Wnt antagonist suppresses the toxic effect of AB on synapses. These findings demonstrate that this Wnt inhibitor is crucial for AB-mediated toxicity on synapses. In this project, we will investigate the contribution of this Wnt antagonist in AB-mediated effect on synapses by taking a combination of cellular, electrophysiological and behavioural approaches. We will also screen for small molecules that interfere with the effect of this antagonist with the aim to develop therapeutic strategies for the prevention and/or treatment of AD. Our studies could also contribute to the identification of diagnostic markers that could be used to detect early stages of AD.

Technical Summary

Alzheimer's disease (AD) is devastating disease that leads to cognitive decline and dementia. It has been estimated that the number of cases of dementia will double in 20 years. Although extensive efforts have been made to find a treatment for this condition, no effective therapies are available.

AD is associated with synaptic dysfunction, the early loss of synapses and the progressive accumulation of Amyloid-Beta (AB) resulting in cognitive decline. Soluble forms of AB decrease the number and strength of synapses before evidence of neuronal cell death. However, the mechanisms by which AB triggers the loss of synapses are poorly understood.

We have recently found that AB interferes with Wnt signalling by inducing the expression of an effective secreted Wnt antagonist. Importantly, this antagonist is required for AB-mediated synaptic loss. In the current proposal, we will examine the contribution of compromised Wnt signalling to AB mediated synaptotoxicity. We will first characterize the role of the Wnt antagonist in AB toxicity by evaluating the integrity of synapses at the cellular and electrophysiological level. We will then examine the in vivo role of this molecule in transgenic mouse models of AD. We will test our hypothesis that expression of the Wnt antagonist in the adult brain might enhance or accelerate synaptic loss and dysfunction in transgenic mouse models of AD. The impact on synapses will be evaluated using a combination of cellular, electrophysiological and behavioural approaches. We will also screen for small molecules that block or interfere with the Wnt antagonist. Our studies could make a significant contribution towards unravelling the mechanisms that trigger synaptic loss in AD, and in the discovery of effective treatment for AD.

Planned Impact

Alzheimer's disease (AD), which represents more than 64% of all types of dementia, is a progressive neurodegenerative disease that sharply increases with age from 8% for people over 65 to 25% for people over 85. It is estimated that 35.6 million people have dementia and this number will double in the next 20 years. In the UK, the societal cost of dementia has been estimated to £ 17.0 billion per year. Thus, AD represents a significant economical and social burden. Despite great progress made in the diagnosis of AD as well as in the cellular and molecular mechanisms that lead to neuronal degeneration, no effective treatments are available to stop or slow down the progression of AD.

Recent evidence has demonstrated that loss and dysfunction of synapses are correlated with cognitive decline. Importantly, increased levels of Amyloid-Beta (AB) contribute to synaptic changes before clear evidence of neuronal degeneration. AB has been shown to regulate the expression and localization of key synaptic proteins. However, it is still unclear how AB affects synapses. Thus, further studies aimed at understanding the mechanisms by which AB affects synaptic structure and function are crucial for developing effective treatment for AD and ideally before cognitive decline is apparent.

Our research group has been studying for many years the role of Wnt secreted proteins in the formation of neuronal circuits in the vertebrate nervous system. Our studies have demonstrated that Wnt signalling promotes the formation of synapses and regulates synaptic strength. More recently we found that Wnts are required for the maintenance of synapses in the adult nervous system. This project led to the discovery that AB rapidly induces the expression of a Wnt antagonist that promotes the disassembly of synapses. Thus, our studies have provided a direct link between decreased Wnt signalling and the loss of synapses initiated by AB.

In this project grant, we aim to fully understand how changes in Wnt signalling contributes to AB-mediated synaptotoxicity in the Alzheimer's brain by taking a multidisciplinary approach. We will use transgenic mouse models of AD to study the in vivo contribution of Wnt signalling to the pathological effects of AB. To evaluate synaptic changes, we will use cellular, electrophysiological and behavioural approaches. We will also screen for small molecules that interfere with the pathogenic effects of AB by blocking Wnt antagonists or by activating Wnt signalling. Biotechnology companies could then use those effective compounds from our screen for translational research.

Our studies will shed new light into the mechanisms by which AB affects synaptic function and stability and therefore will provide clues into how to protect synapses against insult. Work funded under this project grant could also contribute to the development of novel approaches for the treatment of AD as well as other neurodegenerative diseases with accumulation of Amyloid proteins. In addition, our studies could also contribute to the identification of biomarkers that could be used to detect early stages of AD. Therefore, our findings will be of interest to, representatives of the pharmaceutical industry, clinicians, caregivers and patients. The outcome of our experiments using small molecules will be available towards the end of this 3-year project grant. However, their potential application in the clinic might take a number of years even when we are already collaborating with a biotechnology company such as Noscira, which has a Gsk3 inhibitor in phase II clinical trials for AD.

Publications

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Dickins EM (2013) Wnts in action: from synapse formation to synaptic maintenance. in Frontiers in cellular neuroscience

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Hiester BG (2013) Neurotrophin and Wnt signaling cooperatively regulate dendritic spine formation. in Molecular and cellular neurosciences

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McLeod F (2017) Evaluation of Synapse Density in Hippocampal Rodent Brain Slices. in Journal of visualized experiments : JoVE

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Stamatakou E (2013) Activity-dependent spine morphogenesis: a role for the actin-capping protein Eps8. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Stamatakou E (2014) Postsynaptic assembly: a role for Wnt signaling. in Developmental neurobiology

 
Description Dementia Strategy Board at UCL
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
 
Description ERC (European Research Council) Panel Member LS5
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
 
Description MRC board in Neuroscience
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Title Generation of inducible transgenic mice deficient in Wnt signaling to study synapse degeneration 
Description We have generated an inducible transgenic mouse that expresses a Wnt antagonist (Dkk1) in restricted areas of the brain (hippocampus and striatum). When Dkk1 is induced in the adult brain, specific synapses degeneration resulting in long term memory defects and motor defects. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact These mice are now recognised as a model system to study synapse degeneration relevant to early stages of neurodegeneration. 
 
Description Characterization of transgenic mice expressing a Wnt antagonist 
Organisation University of Pennsylvania
Department Department of Dermatology
Country United States 
Sector Academic/University 
PI Contribution We are characterizing transgenic mice expressing a Wnt antagonist in the adult brain
Collaborator Contribution They provided the transgenic mice
Impact We are about to submit a paper reporting the phenotype of the transgenic mice.
Start Year 2010
 
Description The role of Wnt signaling in synaptic connectivity 
Organisation University College London
Department Neuroscience, Physiology & Pharmacology
Country United Kingdom 
Sector Academic/University 
PI Contribution Prof. Alasdair Gibb has been our long-term collaborator. He is expert electrophysiologist who guides my PhD students and postdoc in the use of different electrophysiological techniques
Collaborator Contribution We have published a number of papers together.
Impact This is a multi-disciplinary collaboration.
Start Year 2011
 
Description Help with Athena Swan application in our Division at UCL 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact Involved in the creation of postdoctoral survey to identify areas of needs to increase career progression to young scientists and to improve equality in our division

We are now in the process to provide recommendations to the College
Year(s) Of Engagement Activity 2014
 
Description Interview by Alzheimer's Research Forum 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact We were interviewed by Alzheimer's research forum following our publication in Journal of Neuroscience reporting the Aß induces synapse disassembly through the increased expression of Dkk1

More scientists interested in AD research become aware of our findings.
Year(s) Of Engagement Activity 2012
URL http://www.alzforum.org/new/detail.asp?id=3093
 
Description Parkinson's UK Project visit 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Supporters
Results and Impact Eleven people which included one person from the Parkinson's UK Research team visited our lab in July 2013.
Three lab members gave a presentation of their research followed by a visit of our lab and demonstration of the techniques used in the lab

Several people suffering of PD asked to provide data about our research and findings to discuss with friends and members of their family.
Year(s) Of Engagement Activity 2013
 
Description Public lecture on Parkinson's Disease and Wnt signalling 2013 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Supporters
Results and Impact Around 100 people attended the event. The participants were mainly people with PD or who have a member of their family affected by PD.

People expressed a real interest in our research and wished to visit our lab.
Year(s) Of Engagement Activity 2013
 
Description UCL Parliamentary Reception at the House of Lords Dec 2012 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact UCL Parliamentary Reception organized last December 2012 in the House of Lords. I presented a poster about our work on Wnt signaling and Alzheimer's disease.

Increased awareness on how fundamental research is making an impact in understanding the molecular mechanisms that lead to neurodegeneration. Increased awareness of the importance to support funding organizations such as the MRC.
Year(s) Of Engagement Activity 2012