Understanding Amyloid Post-Translational Modification at the Nanoscale

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Alzheimer's disease is a fatal and incurable form of dementia, affecting 50 million people worldwide. Despite the high prevalence of Alzheimer's disease, currently, there is no cure or biometric diagnostic test for it. Small aggregates of the amyloid-beta peptide, called oligomers, cause toxicity in Alzheimer's disease, and are associated with the disease's onset and progression. Increasing evidence suggest that post-translational modifications alter the propensity of amyloid-beta to aggregate. However, there is currently no information on the implication of such modifications for oligomers' structure and mechanisms, as oligomers are too heterogenous and sparse to be studied with standard methods. To overcome this challenge, we will deliver a novel analytical platform to study oligomers at the single-molecule level. We will combine ultra-sensitive antibody detection via quantitative Polymerase Chain Reaction (qPCR) with super-resolution microscopy and rational drug design to determine how pathological post-translational modifications affect the structure, the toxicity and the druggability of amyloid-beta oligomers. Our results will provide unprecedented information on key mechanisms of Alzheimer's disease and open new clinical intervention.