8AZT

Type II amyloid-beta 42 filaments from high-spin supernatants of aqueous extracts from Alzheimer's disease brains | ABeta42

Summary for 8AZT

• Entry DOI: 10.2210/pdb8azt/pdb
• EMDB information: 15771
• Descriptor: Amyloid-beta precursor protein (1 entity in total)
• Functional Keywords: amyloid, filaments, abeta42, amyloid-beta, cryo-em, protein fibril
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 4520.09

Authors

Yang, Y.,Stern, M.A.,Meunier, L.A.,Liu, W.,Cai, Y.Q.,Ericsson, M.,Liu, L.,Selkoe, J.D.,Goedert, M.,Scheres, H.W.S. (deposition date: 2022-09-06, release date: 2022-11-02, Last modification date: 2024-07-24)

Primary citation

Stern, A.M.,Yang, Y.,Jin, S.,Yamashita, K.,Meunier, A.L.,Liu, W.,Cai, Y.,Ericsson, M.,Liu, L.,Goedert, M.,Scheres, S.H.W.,Selkoe, D.J.
Abundant A beta fibrils in ultracentrifugal supernatants of aqueous extracts from Alzheimer's disease brains.
Neuron, 111:2012-, 2023

PubMed Abstract: Soluble oligomers of amyloid β-protein (Aβ) have been defined as aggregates in supernatants following ultracentrifugation of aqueous extracts from Alzheimer's disease (AD) brains and are believed to be upstream initiators of synaptic dysfunction, but little is known about their structures. We now report the unexpected presence of Aβ fibrils in synaptotoxic high-speed supernatants from AD brains extracted by soaking in an aqueous buffer. The fibrils did not appear to form during preparation, and their counts by EM correlated with Aβ ELISA quantification. Cryo-EM structures of aqueous Aβ fibrils were identical to those from sarkosyl-insoluble homogenates. The fibrils in aqueous extracts were labeled by lecanemab, an Aβ aggregate-directed antibody reported to improve AD cognitive outcomes. Lecanemab provided protection against aqueous fibril synaptotoxicity. We conclude that fibrils are abundant in aqueous extracts from AD brains and have the same structures as those from plaques. These findings have implications for AD pathogenesis and drug design.

PubMed: 37167969
DOI: 10.1016/j.neuron.2023.04.007

Experimental method

ELECTRON MICROSCOPY (3.7 Å)