Reversal of Synapse Degeneration by Restoring Wnt Signaling in the Adult Hippocampus

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.

Rationale for targeting the Wnt signalling modulator Dickkopf‐1 for oncology

“…Although DKK1 clearly regulates Wnt signalling through inhibition of the β‐catenin‐dependent pathway, this may be an oversimplification because DKK1 has also been linked to the activation of β‐catenin‐independent Wnt signalling. For example, DKK1 has been implicated in promoting β‐catenin‐independent Wnt signalling during Xenopus and zebrafish development, neurite outgrowth, in Alzheimer's disease pathogenesis, as well as in oncology models (Pandur et al , ; Caneparo et al , ; Endo et al , ; Thudi et al , ; Wang and Zhang, ; Tao et al , ; Killick et al , ; Krause et al , ; Marzo et al , ). DKK1 activation of β‐catenin‐independent Wnt signalling is not well understood but is probably indirect and involves DKK1 shifting the Wnt signalling balance from the β‐catenin‐dependent pathway to β‐catenin‐independent pathways (discussed in a later section).…”

Pathway-Phenotypes of Non-responders and Partial Responders to Treatment With Antipsychotics in Schizophrenia: A Machine Learning Study

“…DKK1 is an antagonist of the Wnt signaling pathway and, therefore, increases in DKK1 may lead to a breakdown of the blood-brain barrier (43,44). Moreover, DKK1 has neurotoxic effects and may cause a rapid disassembly of the synaptic organization in neurons (45)(46)(47)(48) and lower hippocampal neurogenesis thereby inducing impairments in working memory and memory consolidation (49).…”

Reducing tau ameliorates behavioural and transcriptional deficits in a novel model of Alzheimer’s disease

“…Potential molecular mechanisms linking Aß and tau to synapse and circuit dysfunction include calcium dysregulation and calcineurin activation, which are known to contribute to Aß toxicity and spine collapse in vitro and in vivo and have recently been linked to tau mediated synapse impairment (Hudry et al, 2012;Kuchibhotla et al, 2008;Mattson et al, 1992;Wu et al, 2010;Yin et al, 2016;Zempel et al, 2010). Abnormal activation of synaptic receptors by Aß has also been shown to induce activation of kinases including Fyn and GSK3-ß which affect tau phosphorylation and synapse collapse (Ittner et al, 2010;Lovestone et al, 2014;Marzo et al, 2016;Purro et al, 2012;Roberson et al, 2011;Sellers et al, 2018;Small and Duff, 2008). Our RNAseq results add to the literature implicating cellular prion protein at the interface between Aß and tau as increases in PrPc mRNA in MAPT-AD mice was the largest change observed with RNAseq and these levels recover with tau suppression.…”