Seed-induced acceleration of amyloid-β mediated neurotoxicity in vivo

Seeded propagation of amyloid-beta (A beta) pathology is suggested to contribute to the progression of Alzheimer's disease. Local overproduction of aggregation-prone A beta variants could explain the focal initiation of a seeding cascade that subsequently triggers widespread pathology. Several animal models support this seeding concept by demonstrating accelerated A beta deposition following inoculation with A beta-containing homogenates, however its role in progressive neurodegeneration remains unclear. Here, we present a non-invasive approach to study A beta seeding processes in vivo using Drosophila models. We show that small amounts of aggregation-competent A beta d seeds, generated in selected neuronal clusters, can induce the deposition of the pan-neuronally expressed and otherwise soluble A beta(40). Moreover, our models visualize the accelerated formation and propagation of amyloid pathology throughout the brain, which correlates with severe neurotoxicity. Taken together, these in vivo models provide mechanistic insights into disease-related processes and represent versatile genetic tools to determine novel modifiers of the A beta seeding cascade.