Defining the role of astrocytes in synapse protection in Alzheimer's disease

所有的大脑功能都需要突触的完整性，神经细胞（神经元）之间的专门连接。阿尔茨海默病（AD）是一种破坏性和进行性的神经系统疾病，其特征是认知能力下降，无法形成和保留新的记忆。重要的是，突触丢失是AD认知功能下降的最佳相关因素。在阐明控制突触形成和功能的机制方面取得了重大进展。然而，关于是什么触发了突触丧失以及这一过程是否可以在AD中停止或逆转，人们知之甚少。我们的研究团队一直在研究哺乳动物大脑中一组称为Wnts的蛋白质的功能。我们发现，这些由神经细胞释放的蛋白质促进突触的形成并增加其强度，这对学习和记忆至关重要。我们最近发现，Wnt信号转导在AD中受到损害，因为Wnt的有效抑制剂在AD脑中升高。此外，淀粉样蛋白β（AB）是AD中的一种关键致病分子，它会增加一种名为Dickkopf-1（Dkk 1）的Wnt抑制剂的水平。重要的是，Dkk 1是AB诱导突触丢失所必需的。为了模拟AB在动物体内的作用，我们建立了一种遗传小鼠模型（iDkk 1），该模型在成年大脑的特定区域产生高水平的Dkk 1。我们发现，增加Dkk 1水平会引发突触丢失，严重损害神经元之间的连接，导致记忆缺陷。最近，我们发现iDkk 1小鼠的突触丢失不是渐进的。相反，由于星形胶质细胞的变化，这一过程在最初的突触丧失一段时间后停滞，星形胶质细胞是大脑中接触突触并调节其稳定性和功能的丰富细胞。在iDkk 1小鼠中，在突触丢失的峰值之后，星形胶质细胞与突触接触更多。重要的是，我们发现星形胶质细胞在暴露于Dkk 1时释放保护性突触信号。在这个项目中，我们的目标是解开受体，细胞表面的天线，允许Dkk 1在星形胶质细胞内发出信号，以促进保护性突触信号的合成。我们将首先确定星形胶质细胞中Dkk 1的受体。接下来，我们将利用这些知识来调节动物星形胶质细胞中这些受体的功能。我们的目标是激活星形胶质细胞中的这些受体，以产生保护性突触信号，并测试AD小鼠模型中的突触数量、突触连接和记忆是否恢复。我们将使用多学科的方法，结合分子技术，高分辨率显微镜，电生理学和行为研究。我们的工作将确定保护突触免受退化的新机制，这对开发恢复AD记忆的治疗方法具有重要意义。

All brain functions require the integrity of synapses, specialised connections between nerve cells (neurons). Synapses become weaker and are lost in Alzheimer's disease (AD), a devastating and progressive neurologic condition characterised by cognitive decline and the failure to form and retain new memories. Importantly, synapse loss is the best correlate of cognitive decline in AD. Significant progress has been made in elucidating the mechanisms that control the formation and function of synapses. However, less is known about what triggers synapse loss and whether this process can be halted or reversed in AD. Our research team has been studying the functions of a group of proteins called Wnts in the mammalian brain. We discovered that these proteins, which are released by nerve cells, promote the formation of synapses and increase their strength, which is crucial for learning and memory. We recently found that Wnt signalling is compromised in AD, as potent inhibitors of Wnts are elevated in the AD brain. Moreover, amyloid-beta (AB), a key pathogenic molecule in AD, increases the levels of a Wnt inhibitor called Dickkopf-1 (Dkk1). Importantly, Dkk1 is required for AB to induce synapse loss. To mimic the effect of AB in the animal (in vivo), we generated a genetic mouse model (iDkk1) that makes high levels of Dkk1 in specific areas of the adult brain. We discovered that increasing Dkk1 levels triggers synapse loss, profoundly impairing the connectivity between neurons, leading to memory deficits. More recently, we discovered that synapse loss in iDkk1 mice is not progressive. Instead, this process is stalled after a period of initial synapse loss due to changes in astrocytes, abundant cells in the brain that contact synapses and regulate their stability and function. After the peak of synapse loss, astrocytes make more contact with synapses in iDkk1 mice. Importantly, we discovered that astrocytes release protective synaptic signals when exposed to Dkk1. In this project, we aim to unravel the receptors, antennas on the cell surface, that allow Dkk1 to signal inside astrocytes to promote the synthesis of protective synaptic signals. We will first identify the receptors for Dkk1 in astrocytes. Next, we will use this knowledge to modulate the function of these receptors in astrocytes of the animal. We aim to activate these receptors in astrocytes to produce protective synaptic signals and to test if synapse number, synaptic connectivity, and memory are restored in AD mouse models. We will use a multidisciplinary approach that combines molecular techniques, high-resolution microscopy, electrophysiology, and behavioural studies. Our work will identify novel mechanisms that protect synapses from degeneration, with important implications for developing treatments to restore memory in AD.