Reversal of Synapse Degeneration by Restoring Wnt Signaling in the Adult Hippocampus.
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.
Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
Aude
A
Marzo
Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
Soledad
S
Galli
Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
Douglas
D
Lopes
Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
Faye
F
McLeod
Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
Marina
M
Podpolny
Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
Margarita
M
Segovia-Roldan
Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
Lorenza
L
Ciani
Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
Silvia
S
Purro
Department of Neuroscience, Physiology, and Pharmacology, University College London, London WC1E 6BT, UK.
Francesca
F
Cacucci
Department of Neuroscience, Physiology, and Pharmacology, University College London, London WC1E 6BT, UK.
Alasdair
A
Gibb
Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK. Electronic address: p.salinas@ucl.ac.uk.
Patricia C
PC
Salinas
D000818:Animals; D005260:Female; D006624:Hippocampus / Q000503:physiopathology*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D057567:Memory, Long-Term; D051379:Mice; D008822:Mice, Transgenic; D009473:Neuronal Plasticity; D013569:Synapses / Q000502:physiology*; D060449:Wnt Signaling Pathway
C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins