Analysis of APP and Tau function in exosome and supermere secretion and signalling

Aggregations of the cytoskeletal protein Tau into neurofibrillary tangles and cleavage products of the Amyloid Precursor Protein (APP) into amyloid plaques are strongly associated with the progression of Alzheimer’s Disease (AD). However, it remains unclear whether these aggregates initiate and cause disease or are primarily by-products of more fundamental defects. Furthermore, the physiological and cellular roles of Tau and APP, which might be disrupted in AD, are not well understood.

We have developed a new cell model in the fruit fly, Drosophila melanogaster, to study the normal functions of fly APP and Tau. Remarkably, we find that they are both involved in the biogenesis and secretion of two multimolecular signalling complexes, which are formed in endosomes: exosomes, which are small secreted vesicles, and supermeres, newly identified aggregates of protein and RNA. Their secretion is disrupted when pathological versions of Tau or cleaved APP are expressed in these cells. Using the fly model, we have already identified multiple additional regulators of these APP- and Tau-dependent processes, some of which are implicated in other neurodegenerative diseases. This project will employ neuronal and cancer cell lines to investigate which of these mechanisms are conserved in human cells and how they affect both exosome and supermere signalling. Again, informed by genetic screens in flies, we will then test whether Tau- and APP-induced defects in secretion are suppressed by genetic manipulations of other genes, which might provide new therapeutic targets going forward.