Contribution of Wnt signalling to Amyloid Beta-mediated synaptic dysfunction

阿尔茨海默病(AD)是一种最初以新记忆丧失为特征的疾病，但在后期发展为痴呆症。这种毁灭性的疾病困扰着不同种族、社会和教育背景的人。在所有痴呆症患者中，有超过%的人与AD有关。重要的是，痴呆症病例的数量将在未来20年翻一番，到2050年将翻两番。据估计，2010年，全球痴呆症的成本占全球GDP的1%以上。尽管进行了广泛的研究，但目前还没有有效的治疗AD的方法。因此，AD对我们的社会来说是一个真正的负担和挑战。AD是一种进行性的神经退行性疾病，导致大脑中神经细胞(神经元)的丧失。阿尔茨海默病的一个细胞特征是进行性沉积淀粉样β蛋白，这是AD脑内淀粉样斑块的主要成分。许多研究表明，AB具有很高的致病性，可以诱导神经元死亡。多年来，科学家们一直专注于了解AB是如何诱导神经元退化的。然而，AB斑块的水平与认知能力下降并不完全相关。相比之下，认知和记忆缺陷与突触的丧失有更好的相关性，突触是神经元之间的特殊连接，对大脑功能至关重要。在培养神经元和AD动物模型上的研究表明，在神经元明显死亡之前，AB影响突触的稳定性和功能。然而，AB引起这些突触变化的分子机制还知之甚少。研究调节和促进突触稳定性的分子可以为AB等致病分子影响成年大脑中突触的机制提供重要的见解。我们发现，被称为WNTS的分子促进脊椎动物大脑中突触的形成、生长和维持。最近，我们发现一种分泌蛋白可以阻断WNTS的功能，从而导致突触丢失。重要的是，该因子在AD患者的大脑和暴露于AB的神经元中升高。这些结果表明，AB诱导产生这种Wnt拮抗剂，然后促进突触的丢失。与这一假设一致，我们发现阻断Wnt拮抗剂可以抑制AB对突触的毒性作用。这些发现表明，这种Wnt抑制剂在AB介导的突触毒性中是至关重要的。在这个项目中，我们将采用细胞、电生理和行为相结合的方法来研究这种Wnt拮抗剂在AB介导的突触效应中的作用。我们还将筛选干扰该拮抗剂作用的小分子，目的是开发预防和/或治疗AD的治疗策略。我们的研究也有助于确定可用于检测AD早期阶段的诊断标志物。

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.