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

点击翻译按钮获取中文摘要

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.