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

Conny Leistner, Martin Wilkinson, Ailidh Burgess, Megan Lovatt, Stanley Goodbody, Yong Xu, Susan Deuchars, Sheena E. Radford (), Neil A. Ranson () and René A. W. Frank ()
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Conny Leistner: University of Leeds
Martin Wilkinson: University of Leeds
Ailidh Burgess: University of Leeds
Megan Lovatt: University of Leeds
Stanley Goodbody: University of Leeds
Yong Xu: University of Leeds
Susan Deuchars: University of Leeds
Sheena E. Radford: University of Leeds
Neil A. Ranson: University of Leeds
René A. W. Frank: University of Leeds

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Amyloid plaques composed of Aβ 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 Aβ fibrils in the AppNL-G-F familial AD mouse model containing the Arctic mutation and an atomic model of ex vivo purified Arctic Aβ fibrils. We show that in-tissue Aβ 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 Aβ fibril differs significantly from an earlier AppNL-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 β-amyloid plaque pathology.

Date: 2023
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DOI: 10.1038/s41467-023-38495-5

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