Neurodegenerative diseases are characterised by the accumulation of amyloids in human brain. Cryo-electron microscopy (cryo-EM) of amyloid filaments from post mortem brains has recently shown that distinct amyloid conformations define different neurodegenerative diseases. We describe the structural characterisation of in vitro model systems for amyloid formation that aim to replicate the same structures as observed in diseased brains, with a focus on tau. We show that by using N- and C-terminally truncated tau constructs, under specific conditions can lead to structures like those observed in Alzheimer’s Disease (AD) and Chronic Traumatic Encephalopathy (CTE). We show that NMR and high through-put cryo-EM approaches can be used to study the molecular mechanisms of amyloid assembly. We show that amyloid-prone regions within the tau sequence can form dimers in solution which assemble into protofibril structures. These protofibrils are intermediate filament structures which can rearrange into mature filaments, like those observed in disease.
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|Modern Methods in Structural Biology and Dynamics