We recently published a paper in eLife entitled “Downregulation of Dickkopf-3, a Wnt antagonist elevated in Alzheimer’s disease, restores synapse integrity and memory in a disease mouse model”. Alzheimer’s disease (AD) is the most common form of dementia worldwide. Synapse dysfunction is one of the earliest hallmarks of AD, but the mechanisms involved are not fully understood. Deficient Wnt signalling, a pathway that is crucial for the maintenance of neuronal circuits, has been linked to synapse dysfunction and loss in AD. Recent work showed that DKK3, a secreted protein that negatively regulates Wnt signalling, is present in amyloid-β aggregates that typically form in the brain of AD patients. However, the function of DKK3 in the adult brain and its role in AD remained unexplored. In this study, we provide new evidence that DKK3 levels increase in the human AD brain with the progression of the disease. Using functional and mechanistic approaches, we demonstrate a novel role for DKK3 in regulating excitatory and inhibitory synaptic integrity. Gain of function of DKK3 decreases excitatory synapse but increases inhibitory ones. Importantly, we discover that downregulation of DKK3 restores synapse number and memory in an AD mouse model. These findings further our understanding of the molecular mechanisms contributing to synaptic impairment in Alzheimer’s disease and demonstrate that activation of Wnt signalling is a potential therapeutic approach to restore neuronal connectivity in AD.
Author: Salinas_Lab_UCL
Our work has been featured on the UCL website!
Our work on the LRP6 Val variant, recently published in Science Advances, has been featured on the UCL website. Check out the link below!
Check out our latest paper on the impact of Wnt receptor variant LRP6 Val and the links between synaptic connectivity in ageing and in AD
We are pleased that our paper on the LRP6 Val variant has been published in Science Advances.
We identified that carrying this variant of LRP6 enhances synaptic defects and synapse loss during ageing and increases synapse degeneration in Alzheimer’s disease. These changes in connectivity could result in a detrimental effect on cognitive function in human carriers of the LRP6 variant. The study also identified that the mutant receptor does not initiate Wnt signalling or promote synapse formation in response to Wnt proteins.
Together, our study provides new insights into potential targets for promoting synapse repair/recovery in Alzheimer’s disease.
Check out our latest paper on epigenetic repression of Wnt receptors in AD
We are excited to share our latest paper published in Molecular Psychiatry on epigenetic repression of Wnt receptors in AD. We define a novel role for nuclear hyperactivated Sirt2 in repressing Fzd1 and Fzd7 expression via H4K16ac deacetylation in AD. We propose Sirt2 as an attractive target to ameliorate AD pathology.
Check out our latest paper on the interplay between Wnt, NOS and LTP
We are excited to share our newest publication on the effects of nitric oxide signalling on the formation of multi-innervated spines. We found that Wnt7a stimulates the formation of MISs via the activation of postsynaptic Dvl1 and retrograde nNOS signalling. The results are published in Frontiers in Synaptic Neuroscience (link).
You can find this and the rest of our publications on our Publications page.
Check out our latest paper describing a role for Wnts in synaptic plasticity
Patricia Molina Molina awarded best overall student for Neuroscience MSc Degree 2017
We congratulate our past student Patricia Molina Molina on her Neuroscience MSc distinction and for winning the best overall student. Good luck in your PhD at the Institute of Neurosciences, Universitat Autònoma de Barcelona.
Postdoctoral Fellow Awarded the UCL Neuroscience Early Career prize
Dr Aude Marzo, a postdoctoral fellow in the lab, was awarded the UCL Neuroscience Early Career prize (June 2017) in the Advanced Category. This award was based on her work recently published in Current Biology. (http://www.ucl.ac.uk/research/domains/neuroscience/events/2017NeuroscienceSymposium)
Postdoctoral Fellow Awarded EU H2020 Marie Curie Fellowship
Dr Ernest Palomer-Villa, a postdoctoral fellow in the lab, was awarded EU H2020 Marie Curie Fellowship to work on the mechanisms that lead to the deregulation of Wnt components in Alzheimer’s disease.
