Abstract
The molecular mechanisms that regulate synapse formation have been well documented. However, little is known about the factors that modulate synaptic stability. Synapse loss is an early and invariant feature of neurodegenerative diseases including Alzheimer's (AD) and Parkinson's disease. Notably, in AD the extent of synapse loss correlates with the severity of the disease. Hence, understanding the molecular mechanisms that underlie synaptic maintenance is crucial to reveal potential targets that will allow the development of therapies to protect synapses. Wnts play a central role in the formation and function of neuronal circuits. Moreover, Wnt signaling components are expressed in the adult brain suggesting their role in synaptic maintenance in the adult. Indeed, blockade of Wnts with the Wnt antagonist Dickkopf-1 (Dkk1) causes synapse disassembly in mature hippocampal cells. Dkk1 is elevated in brain biopsies from AD patients and animal models. Consistent with these findings, Amyloid-β (Aβ) oligomers induce the rapid expression of Dkk1. Importantly, Dkk1 neutralizing antibodies protect synapses against Aβ toxicity, indicating that Dkk1 is required for Aβ-mediated synapse loss. In this review, we discuss the role of Wnt signaling in synapse maintenance in the adult brain, particularly in relation to synaptic loss in neurodegenerative diseases.
Highlights
Appropriate formation, maintenance, and elimination of synapses are crucial to guarantee the formation of a functional nervous system
In contrast to Wnt7a, Wnt5a induces postsynaptic assembly and increases the levels of g-aminobutyric acid type a (GABAA) receptors by activating non-canonical Wnt signaling in hippocampal neurons (Farias et al, 2009; Cuitino et al, 2010; Varela-Nallar et al, 2010)
Given that the effect of Dkk1 can be reverted by Wnts or inhibition of glycogen synthase kinase-3 (Gsk3), these findings strongly suggest that endogenous Wnts expressed by mature neurons are crucial for the maintenance of synaptic connections in the adult brain
Summary
Appropriate formation, maintenance, and elimination of synapses are crucial to guarantee the formation of a functional nervous system. Wnts, their receptors, and many of the components of the signaling pathway are expressed in the adult brain, suggesting that they might have a role in synaptic stability. We review recent studies that strongly suggest a role of Wnt signaling in the maintenance of synapses in the adult brain and indicate that dysfunction of Wnt signaling may contribute to the loss of synapses in AD.
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