Deficiency in Wnt signalling and synapse degeneration: implications in Alzheimer's disease
Wnt secreted proteins play a crucial role in synapse formation and growth. Recent studies from our lab indicate that Wnts promote synaptic stability in the adult brain. Given that several studies suggest that dysfunction in Wnt signalling contributes to the pathogenesis of Alzheimer’s disease (AD), we begun to investigate how deficits in Wnt signalling could contribute to synaptic degeneration manifested at early stages in AD before cell death is evident. Several studies have shown that the specific and effective Wnt antagonist Dickkopf-1 (Dkk1) is elevated in the brains of AD patients and in transgenic animal models of AD. Interestingly, we found that Amyloid-ß (Aß) peptides rapidly increase the level of Dkk1 in brain slices at the time when synapses disassemble. Importantly, blockade of Dkk1 completely suppresses the toxic effect of Aß on synapses demonstrating the Dkk1 is downstream of Aß to induce synapse vulnerability. To examine the in vivo role of Wnt signalling in synapse stability, we have generated a transgenic mouse line that inducible expresses Dkk1 in the adult hippocampus. Our studies demonstrate that adult expression of Dkk1 leads to the specific loss of excitatory synapses, induces profound defects in synaptic transmission and deficits in long-term memory. These studies demonstrate for the first time that deficiency in Wnt signalling in the adult brain results in profound changes in synaptic stability and function resulting in cognitive deficits. I will discuss the potential implications of our findings in synapse degeneration at early stages of Alzheimer’s disease.