The inter-organelle cross-talk finely orchestrated in the amyloidogenic processing of amyloid precursor protein in dendritic arborization neurons of <i>Drosophila</i>

<b>Background:</b> Organelles in neuronal dendrites facilitate local metabolic processes and energy supply, crucial for dendrite development and neurodegenerative diseases. The distinct functions of dendritic organelles have been well studied, however, their crosstalk under physiological and pathological contexts remains elusive. We aimed to establish an <i>in vivo</i> model system of contacts between multi-organelles for investigating the modulation of inter-organelle crosstalk in Alzheimer's disease (AD). <b>Methods:</b> A dendrite model of organelle contacts was developed in <i>Drosophila</i> neurons using a set of proximity-driven probes and four-color Airyscan super-resolution imaging. The systematic modulations among multiple contact sites (CSs) between organelles were examined by manipulating CS tethers and vesicular transporters. Finally, perturbations of these CSs and the dendrite structure in the amyloidogenic processing of amyloid precursor protein (APP) were evaluated by introducing three stages of the processing in this model system. <b>Results:</b> A dynamic network, interconnected via CSs and organized with multi-organelle contacts, was presented among Golgi outposts, the endoplasmic reticulum, lysosomes, and mitochondria (GELM). The CS modulations were found to encompass both their density and motility. Notably, multi-CSs participated in complementary modulations spanning across different cellular pathways. Furthermore, the CS network was revealed to be progressively disturbed in APP amyloidogenic processing, with upregulations in density and motility extending from single- to multi-CSs. These CS perturbations, along with defects in dendrite structural plasticity, could be partially rescued by knocking down Miro. <b>Conclusion:</b> The elucidation of CS modulation modes in the GELM network model reveals a cascaded dysregulation of organelle crosstalk during APP amyloidogenic processing. It expands the mechanisms of inter-organelle communication and provides novel insights into neurodegeneration in AD pathology.