Defining the role of astrocytes in synapse protection in Alzheimer's disease
Lead Research Organisation:
University College London
Department Name: Cell and Developmental Biology
Abstract
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.
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.
Technical Summary
Synapse degeneration is an early event in Alzheimer's disease (AD) that contributes to cognitive decline. Amyloid beta (AB), a key pathogenic molecule in AD, triggers synapse degeneration by interfering with synaptic signals critical to synaptic integrity. AB affects synapses by acting directly on neurons and through glial cells. Despite extensive studies, our understanding of how synapses are affected and the role of astrocytes in AD remains limited.
Wnts are secreted proteins that regulate synapse formation, maintenance, and synaptic function in the brain. Several studies show that deficient Wnt signalling contributes to AB-mediated synapse loss. Indeed, the Wnt antagonist Dickkopf-1 (Dkk1) is elevated in the human AD brain and is required for AB-mediated synapse degeneration.
To mimic the effect of AB on Dkk1, we generated a genetic mouse model that inducibly expresses Dkk1 (iDkk1 mice) in the adult brain. After 14 days of Dkk1 induction, 40% of synapses are lost. However, synapse degeneration is not progressive. Interestingly, astrocyte changes are observed at this stage but not before. Astrocytes regulate many aspects of synapse biology, and their end-feet are closely associated with synapses. In iDkk1 mice, astrocyte end-feet wrap around more synapses at the peak of synapse degeneration. Importantly, we found that astrocytes exposed to Dkk1 release protective synaptic signals. Thus, astrocytes protect the remaining synapses to halt further synapse degeneration.
The aim of this project is to identify the Dkk1 receptors in astrocytes and use this knowledge to modulate astrocyte function in AD mouse models to restore synapse number, synaptic connectivity and memory. Using a multidisciplinary approach that combines molecular techniques, proteomic analyses, super-resolution microscopy, electrophysiology and behaviour, our studies will provide new mechanistic insights into how synapses can be protected, and cognitive function restored in AD.
Wnts are secreted proteins that regulate synapse formation, maintenance, and synaptic function in the brain. Several studies show that deficient Wnt signalling contributes to AB-mediated synapse loss. Indeed, the Wnt antagonist Dickkopf-1 (Dkk1) is elevated in the human AD brain and is required for AB-mediated synapse degeneration.
To mimic the effect of AB on Dkk1, we generated a genetic mouse model that inducibly expresses Dkk1 (iDkk1 mice) in the adult brain. After 14 days of Dkk1 induction, 40% of synapses are lost. However, synapse degeneration is not progressive. Interestingly, astrocyte changes are observed at this stage but not before. Astrocytes regulate many aspects of synapse biology, and their end-feet are closely associated with synapses. In iDkk1 mice, astrocyte end-feet wrap around more synapses at the peak of synapse degeneration. Importantly, we found that astrocytes exposed to Dkk1 release protective synaptic signals. Thus, astrocytes protect the remaining synapses to halt further synapse degeneration.
The aim of this project is to identify the Dkk1 receptors in astrocytes and use this knowledge to modulate astrocyte function in AD mouse models to restore synapse number, synaptic connectivity and memory. Using a multidisciplinary approach that combines molecular techniques, proteomic analyses, super-resolution microscopy, electrophysiology and behaviour, our studies will provide new mechanistic insights into how synapses can be protected, and cognitive function restored in AD.
