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

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...

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Bibliographic Details
Published in:Nature Communications
Main Authors: Conny Leistner, Martin Wilkinson, Ailidh Burgess, Megan Lovatt, Stanley Goodbody, Yong Xu, Susan Deuchars, Sheena E. Radford, Neil A. Ranson, René A. W. Frank
Format: Article in Journal/Newspaper
Language:English
Published: Nature Portfolio 2023
Subjects:
Science
Q
Arctic
Online Access:https://doi.org/10.1038/s41467-023-38495-5
https://doaj.org/article/1dd0f73ed8e440b4a6e25d4257c0c4dc
Description
Summary: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 App NL-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 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 β-amyloid plaque pathology.

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