Summary: Researchers have been able to successfully reverse memory loss in mice following the discovery about a key mechanism that underlies the loss of neuronal connectivity.
Source: UCL
Memory loss in mice has been successfully reversed following the discovery of new information about a key mechanism underlying the loss of nerve connectivity in the brain, say UCL researchers.
Published today in Current Biology, the study funded by Alzheimer’s Research UK, Parkinson’s UK, Wellcome, MRC and the EU investigated the mechanism driving communication breakdown in adult brains – specifically, the loss of connections between nerve cells in the hippocampus, an area of the brain that controls learning and memory. The team found Wnt proteins play a key role in the maintenance of nerve connectivity in the adult brain and could become targets for new treatments that prevent and restore brain function in neurodegenerative diseases.
The breakdown of connections between nerve cells is an early feature of diseases like Alzheimer’s and is known to cause distressing symptoms like memory and thinking decline, but the biological processes behind it are poorly understood. Nerve cells are connected at communication points called synapses and the slow degeneration of these connections is an important area of study for researchers looking to slow or stop Alzheimer’s disease.
Lead author, Professor Patricia Salinas (UCL Cell & Developmental Biology), said: “Synapses are absolutely critical to everything that our brains do. When these important communication points are lost, nerve cells cannot exchange information and this leads to symptoms like memory and thinking problems. The Wnt pathway is emerging as a key player in the regulation of the formation, maintenance and function of synapses, and we have provided strong evidence that the Wnt proteins are also critical for memory.
“Understanding the role of Wnts in Alzheimer’s disease is an important next step, as there is potential we could target this chain of events with drugs. Preventing or reversing the disruptions in connectivity and communication between nerve cells in Alzheimer’s would be a huge step forward.”
Increasing evidence suggests that deficiency in Wnt function contributes to disruption of brain connectivity in Alzheimer’s disease and therefore resulting in memory loss. The team studied the impact of a protein called Dkk1, known to block the action of Wnts and found at higher levels in people with Alzheimer’s, in brain circuits and memory.
Genetically modified mice in which Dkk1 can be switched on, disrupting the action of Wnts and its downstream chain of events were used. To avoid any disruption to normal brain development driven by Wnts and Dkk1, the researchers waited until the mice were adults before switching on Dkk1 in an area of the brain important for the formation of new memories.
When Dkk1 was switched on in the adult mice, the researchers found the mice had memory problems, and that this coincided with the presence of fewer synapses between nerve cells, indicating a communication breakdown. However, when the researchers switched Dkk1 back off, the mice no longer had memory problems, the number of synapses increased back to normal levels and brain circuits were restored.
Dr Simon Ridley, Director of Research at Alzheimer’s Research UK, said: “This study in mice adds further weight to a growing body of evidence implicating Wnts and its related proteins to nerve cell connectivity and memory. By understanding mechanisms driving healthy nerve cells, we can best unpick what happens when these processes go so wrong.
“This research sets a solid foundation for future work to explore the role of Wnts in diseases like Alzheimer’s, and this biological process is already a key target being explored by expert teams in the Alzheimer’s Research UK Drug Discovery Alliance. Researchers are taking huge steps forward in their understanding of what happens in the brain in health and disease, and we must now capitalise on these discoveries to deliver effective treatments that can transform lives.”
Funding: This work was supported by Alzheimer’s Research UK, Parkinson’s UK, Wellcome, MRC and the EU.
Source: Bex Caygill – UCL
Image Source: NeuroscienceNews.com image is adapted from the UCL press release.
Original Research: Full open access research for “Reversal of Synapse Degeneration by Restoring Wnt Signaling in the Adult Hippocampus” by Aude Marzo, Soledad Galli, Douglas Lopes, Faye McLeod, Marina Podpolny, Margarita Segovia-Roldan, Lorenza Ciani, Silvia Purro, Francesca Cacucci, Alasdair Gibb, and Patricia C. Salinas in Current Biology. Published online September 1 2016 doi:10.1016/j.cub.2016.07.024
[cbtabs][cbtab title=”MLA”]UCL “Memory Loss Reversed: Key Mechanism Behind Brain Connectivity and Memory Revealed.” NeuroscienceNews. NeuroscienceNews, 2 September 2016.
<https://neurosciencenews.com/memory-connectivity-neuroscience-4954/>.[/cbtab][cbtab title=”APA”]UCL (2016, September 2). Memory Loss Reversed: Key Mechanism Behind Brain Connectivity and Memory Revealed. NeuroscienceNew. Retrieved September 2, 2016 from https://neurosciencenews.com/memory-connectivity-neuroscience-4954/[/cbtab][cbtab title=”Chicago”]UCL “Memory Loss Reversed: Key Mechanism Behind Brain Connectivity and Memory Revealed.” https://neurosciencenews.com/memory-connectivity-neuroscience-4954/ (accessed September 2, 2016).[/cbtab][/cbtabs]
Abstract
Reversal of Synapse Degeneration by Restoring Wnt Signaling in the Adult Hippocampus
Highlights
•Wnt signaling is required for synapse integrity in the adult hippocampus
•Dkk1 induces synapse loss and deficits in synaptic plasticity and long-term memory
•Dkk1 disassembles synapses by activating the Gsk3 and Rock pathways
•Synapse loss and memory defects are reversible by reactivation of the Wnt pathway
Summary
Synapse degeneration occurs early in neurodegenerative diseases and correlates strongly with cognitive decline in Alzheimer’s disease (AD). The molecular mechanisms that trigger synapse vulnerability and those that promote synapse regeneration after substantial synaptic failure remain poorly understood. Increasing evidence suggests a link between a deficiency in Wnt signaling and AD. The secreted Wnt antagonist Dickkopf-1 (Dkk1), which is elevated in AD, contributes to amyloid-β-mediated synaptic failure. However, the impact of Dkk1 at the circuit level and the mechanism by which synapses disassemble have not yet been explored. Using a transgenic mouse model that inducibly expresses Dkk1 in the hippocampus, we demonstrate that Dkk1 triggers synapse loss, impairs long-term potentiation, enhances long-term depression, and induces learning and memory deficits. We decipher the mechanism involved in synapse loss induced by Dkk1 as it can be prevented by combined inhibition of the Gsk3 and RhoA-Rock pathways. Notably, after loss of synaptic connectivity, reactivation of the Wnt pathway by cessation of Dkk1 expression completely restores synapse number, synaptic plasticity, and long-term memory. These findings demonstrate the remarkable capacity of adult neurons to regenerate functional circuits and highlight Wnt signaling as a targetable pathway for neuronal circuit recovery after synapse degeneration.
“Reversal of Synapse Degeneration by Restoring Wnt Signaling in the Adult Hippocampus” by Aude Marzo, Soledad Galli, Douglas Lopes, Faye McLeod, Marina Podpolny, Margarita Segovia-Roldan, Lorenza Ciani, Silvia Purro, Francesca Cacucci, Alasdair Gibb, and Patricia C. Salinas in Current Biology. Published online September 1 2016 doi:10.1016/j.cub.2016.07.024
