The role of the cytoskeleton in Alzheimer's disease: a Drosophila perspective

Abstract

Alzheimer's disease (AD) pathogenesis is likely to be caused by dysfunction of two neuronal proteins, amyloid-beta (Aβ) and tau. Whilst excellent in vivo assays have been performed, and animal models which develop pathology which resembles AD have been generated, the cellular events that lead to neurodegeneration remain poorly understood, in particular those which involve the cytoskeleton. Microtubules (MTs) are vital for many axonal functions, including growth and transport. MTs have been implicated in neurodegeneration; 44% of cytoskeletal genes have OMIM links to human disorders, and over half of those disorders result in neuronal dysfunction. Aβ and tau are well understood biochemically, but the functional links between these proteins, and how they cause neurodegeneration, remain poorly understood. In the context of AD, Aβ and tau are known to have numerous toxic effects which could have extensive influence on the function of the cytoskeleton; a system which is essential in neurons. Here I utilise Drosophila primary neuron culture in order to determine the subcellular phenotypes associated with the application of Aβ via different genetic and artificial means, in concert with human tau (hTau), in a comparative analysis. I have demonstrated that fly neuron culture is suited in this capacity, and have demonstrated that different methods of Aβ and hTau application to neurons elicit different phenotypes, in particular regarding the timing and extent of MT disorganisation, and suggest that there may be qualitative reasons for the different phenotypes between the approaches taken.

Date of Award	1 Aug 2016
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Andreas Prokop (Supervisor) & Andrew Doig (Supervisor)