The in-tissue molecular architecture of -amyloid pathology in the mammalian brain

In this work the authors reveal in-situ cryoET characterization of beta-amyloid plaques in the brain of a mouse model of Alzheimer's disease. Amyloid plaques composed of A beta fibrils are a hallmark of Alzheimer's disease (AD). However, the molecular architecture of amyloid plaques in the context of fresh mammalian brain tissue is unknown. Here, using cryogenic correlated light and electron tomography we report the in situ molecular architecture of A beta fibrils in the App(NL-G-F) familial AD mouse model containing the Arctic mutation and an atomic model of ex vivo purified Arctic A beta fibrils. We show that in-tissue A beta fibrils are arranged in a lattice or parallel bundles, and are interdigitated by subcellular compartments, extracellular vesicles, extracellular droplets and extracellular multilamellar bodies. The Arctic A beta fibril differs significantly from an earlier App(NL-F) fibril structure, indicating a striking effect of the Arctic mutation. These structural data also revealed an ensemble of additional fibrillar species, including thin protofilament-like rods and branched fibrils. Together, these results provide a structural model for the dense network architecture that characterises beta-amyloid plaque pathology.