Seed-induced acceleration of amyloid-ß mediated neurotoxicity in vivo.

ABSTRACT

Seeded propagation of amyloid-beta (Aß) pathology is suggested to contribute to the progression of Alzheimer's disease. Local overproduction of aggregation-prone Aß 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 Aß deposition following inoculation with Aß-containing homogenates, however its role in progressive neurodegeneration remains unclear. Here, we present a non-invasive approach to study Aß seeding processes in vivo using Drosophila models. We show that small amounts of aggregation-competent Aß42 seeds, generated in selected neuronal clusters, can induce the deposition of the pan-neuronally expressed and otherwise soluble Aß40. 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 Aß seeding cascade.Seeding of amyloid beta from one brain region to another is thought to contribute to the progression of Alzheimer's disease, although to date most studies have depended on inoculation of animals with exogenous amyloid. Here the authors describe a genetic seed and target system in Drosophila which may be useful for the mechanistic study of seeding of amyloid in vivo.