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Protein misfolding in Alzheimer’s disease

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If you have a question about this talk, please contact Dr Georg Meisl.

Protein misfolding is central to many diseases including Alzheimer’s disease. However, the mechanism by which conformational change is initiated remains elusive. Alzheimer’s disease is characterised by key proteins including Tau, Amyloid-beta and by the risk factor isoform Apolipoprotein E4. However, the role of each of these in the neurodegenerative disease cascade is unclear. Our work aims to explore the initiation events that lead to misfolding and the downstream effects on neuronal function, whilst clarifying the potentially toxic species. In this talk, I will describe work that aims to uncover fundamental mechanisms at the heart of the structural changes in Amyloid-beta, tau and ApoE4.

ApoE is the major genetic risk factor for developing AD. Despite decades of research, the way in which ApoE exerts its effect remains elusive. We have recently compared and characterised the three isoforms of ApoE and show that ApoE4 is able to self-assemble into non-amyloid-like filaments. Tau is a natively unfolded protein which, unlike Amyloid-beta, does not readily self-assemble. We have developed a model fragment which self-assembles to form paired helical filaments in vitro which we have used to examine cellular mechanisms of transmission and toxicity. Amyloid beta rapidly self-assembles and oligomeric species have been previously shown to affect neuronal health. We have studied the uptake and effects on organelles including lysosomes, synaptic vesicles and mitochondria to dissect mechanisms that lead to neuronal dysfunction and cell death. We reveal damage to specific organelles of the cell which are accompanied by impaired synaptic vesicle release and reuptake. We consider the underlying mechanisms that may consolidate these findings and explore potential therapies.

This talk is part of the Biophysical Seminars series.

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