Abstract

Tauopathies are neurodegenerative diseases, most often linked to dementia, that are associated with aberrant forms of the cytoskeletal protein, tau. In many tauopathies, but particularly Alzheimer’s Disease, synapse dysfunction is a prominent feature early in disease progression. In mouse models of tauopathy, pathological tau is localised to postsynaptic sites in many, but not all, synapses. We hypothesise that it is the local presence of tau at individual synapses that drives their dysfunction and that variation in synaptic localisation of tau underlies differences in the apparent pathology of different synapses, even within the same neuron. To address this hypothesis, using a mouse model of neurodegenerative tauopathy, we will image tau localisation and the structure of dendritic spines, which are the sites of excitatory synapses, using a new super-resolution imaging technique called Expansion Microscopy. High resolution structural measures afforded by this type of analysis will establish whether dendritic spine structure is altered when aberrant tau is located nearby. Since dendritic spine structure is intimately linked to synapse function, any relationship between tau and structure would lead to testable hypotheses linking local tau to individual synaptic dysfunction.