Clive Wilson - Neuroscience - 'Regulation of physiological and pathological amyloidogenesis in Alzheimer’s disease and beyond'

Amyloidogenesis, the aggregation of soluble proteins into insoluble fibrils, has multiple biological functions in health and disease, eg, in Alzheimer’s Disease (AD), aggregations of A-beta peptides, cleaved products of Amyloid Precursor Protein (APP), form plaques, while peptide hormones naturally condense into insoluble, dense-core granules (DCGs), stored within secretory vesicles until release. However, in vivo assays to analyse how amyloidogenesis is initiated are lacking. We have developed a new cellular model for DCG biogenesis, the Drosophila prostate-like secondary cell (SC). These cells have highly enlarged (5 micron diameter) DCG compartments, permitting the rapid process of DCG assembly to be followed by light and fluorescence microscopy in real-time. We find DCG formation requires the fly homologues of APP, called APPL, and another amyloidogenic protein, TGF-beta-induced, as well as intraluminal vesicles that are secreted as so-called Rab11-exosomes. Genetic dissection of the DCG biogenesis process in SCs shows that it is disrupted by mutant proteins linked to AD, including A-beta peptides and Tau, producing several AD-like phenotypes, and strongly suggests that these previously unappreciated defects are key triggers in pathology. This project will characterise this process further in flies and investigate how pathological defects can be suppressed by genetic manipulations, drugs and dietary changes. See https://www.biorxiv.org/content/10.1101/2024.03.28.586966v2 for recent developments.