Alzheimer's Disease (AD) is characterised by two histopathological hallmarks, intracellular tau-containing neurofibrillary tangles and extracellular amyloid plaques containing {beta}-amyloid (A{beta}), a specific cleavage product of Amyloid Precursor Protein (APP). Initiation of A{beta}-induced neuronal pathology, however, has been postulated to involve intracellular events affecting endolysosomal trafficking that can propagate between cells. Recent studies in non-neuronal Drosophila secondary cells (SCs) have revealed that A{beta} interferes with APP-regulated protein aggregation events, which package signalling molecules into insoluble dense-core granules (DCGs) during normal regulated secretion, inducing endolysosomal defects that are transferred to other cells. Here, using SCs, we show that knockdown of the gene encoding accessory ESCRT-III protein Chmp5, which selectively regulates the formation of intraluminal vesicles (ILVs) inside SC DCG compartments that are subsequently released as Rab11-exosomes, inhibits propagation of A{beta}-induced endolysosomal trafficking defects. Furthermore, knocking down Chmp5 or other accessory ESCRT-III genes also suppresses A{beta}-induced, neurodegeneration-dependent morphological defects in the Drosophila eye. We conclude that genes controlling the Rab11-exosome biogenesis pathway play a key role in both A{beta}-induced endolysosomal trafficking defects associated with aberrant regulated secretion and cellular events leading to neurodegeneration. Our findings indicate these processes are linked and may suggest new target pathways for future development of AD therapeutics.
Cording, A., Verma, B., Arous, A., Rice, S., Vine, H., Blincowe, L., Wainwright, S. M., Singh, P. J., Goberdhan, D. C. I., Wilson, C.
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