Abstract
SummarySynapse 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.
Highlights
Synapse loss and dysfunction are an early occurrence in several neurodegenerative conditions, including Alzheimer’s disease (AD)
Inducible Dkk1-Expressing Mice as a Model for Wnt Deficiency in the Adult Brain To investigate the contribution of Wnt signaling to synapse maintenance in the adult hippocampus, we took advantage of a transgenic mouse model where expression of a potent and specific secreted Wnt antagonist, Dkk1, is controlled under the tetracycline-inducible system and CaMKII promoter [22]
Expression of Dkk1 is induced in adult mice by administration of doxycycline, bypassing any potential deleterious effects of deficient Wnt signaling during embryogenesis and postnatal development, stages when Wnt signaling plays a critical role [12, 23,24,25]
Summary
Synapse loss and dysfunction are an early occurrence in several neurodegenerative conditions, including Alzheimer’s disease (AD). Increasing evidence suggests that deficient canonical Wnt signaling contributes to AD pathogenesis. Loss of function of LRP6 in hippocampal neurons results in synaptic defects, cell death, and exacerbation of amyloid deposition in a mouse model of AD [10]. The secreted protein Dickkopf-1 (Dkk1), which blocks canonical Wnt-Gsk signaling by sequestering the LRP6 receptor [11, 12], is elevated in post-mortem brains from AD patients and in AD animal models [13,14,15]. Blockade of Dkk with neutralizing antibodies protects synapses from Ab-mediated disassembly [17]. These results suggest that Dkk1-mediated deficiency of Wnt signaling could contribute to synapse vulnerability. The impact of Dkk on hippocampal circuits, which are severely affected in AD, and its mechanism of action have not been explored
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