Cellular mechanisms facilitating the spreading of Tau pathology in Alzheimer's disease: uptake, release and synaptic cell-to-cell transmission of Tau nano-aggregates in neuronal networks

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In Alzheimer’s disease (AD) and other dementia diseases, abnormal Tau protein aggregation spreads through-out the patient’s brain. Thereby, the progression of Tau pathology follows a certain pattern and correlates with the stage of neurodegeneration. In AD brains, long fibrillar aggregates of otherwise soluble Tau accumulate in neurofibrillar tangles (NFTs). However, small soluble nano-aggregates of Tau and other proteins are recently discussed as infective and toxic species in various neurodegenerative diseases such as AD, Parkinson’s and prion diseases. The aim of this project is to examine whether and how soluble Tau nano-aggregates trigger the intracellular aggregation of neuronal Tau and travel through neuronal networks. To study the mechanisms of cellular uptake, release and synaptic neuron-to-neuron transmission of Tau aggregates, mouse neurons will be cultured in custom-made microfluidic devices that enable us to generate minimal, two-neuron networks. Using fluorescence-based Tau aggregation assays, high-resolution light-microscopy and different biophysical methods we will elucidate the role of soluble Tau aggregates in AD on the single cell level. Our results will enlighten the cellular processes behind progressive protein aggregation in neurodegenerative diseases.