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Investigating neuronal delta-catenin and the amyloid-beta mediated pathophysiology of Alzheimer’s disease


Faculty of Health Sciences

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Dr D Whitcomb , Prof K Cho Applications accepted all year round Self-Funded PhD Students Only

About the Project

Description

Extensive evidence suggests that soluble oligomeric forms of amyloid-β protein (Aβ) are neurotoxic and lead to synaptic dysfunction in Alzheimer’s disease (AD). In particular, synapse degradation and elimination appears to be a crucial element in the pathophysiology of the disease. Indeed, we have previously shown that the activation of caspase-3 and GSK-3β by Aβ is a central aspect of Aβ-mediated dysregulation of neuronal function (Jo et al., 2011). However, the full extent of the mechanisms by which Aβ causes synapse impairment and ultimately synapse removal, remain to be fully understood.

δ-catenin is a 130 kDa member of the p120 subclass of catenin proteins, which are a family characterised by ten Armadillo repeats. Catenins have been canonically implicated in cell adhesion, functioning intracellularly to bind cadherin cytoplasmic domains. It has more recently been shown that δ-catenin is found in dendrites and spines of mature neurons (Kosik et al., 2005). Critically, a recent publication has revealed a possible role for δ-catenin in regulating synapse function in hippocampal neurons, where δ-catenin was shown to be critical in controlling synaptic glutamate receptor expression (Brigidi et al., 2014). We have recently found that Aβ exposure induces the degradation of δ-catenin in neurons. We now want to explore whether this effect of Aβ on δ-catenin is implicated in the Aβ-mediated pathophysiology of hippocampal neurons.

This project will take a multidisciplinary approach, bringing together brain-slice electrophysiology, in vitro molecular biology tissue analysis and high-resolution imaging techniques. The student will learn a range of investigative techniques, including extracellular field potential recording, whole-cell patch clamp recording, organotypic brain slice culture, Western blot and confocal imaging.

References

Brigidi et al. (2014). Nat. Neurosci. 17, 522-32.

Jo et al. (2011). Nat. Neurosci. 14, 545-7.

Kosik et al. (2005). Trends Cell Biol. 15, 172-78.


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