Contribution of Wnt signalling to Amyloid Beta-mediated synaptic dysfunction

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.

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.

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.