Science - USA (2022-01-14)

of major RNA viruses, making it a promising
therapeutic option for RSV disease and COVID-
19, and a much-needed contributor to im-
provement of pandemic preparedness.

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ACKNOWLEDGMENTS
We thank C. F. Basler for providing the Calu-3 cells, D. Waugh for
plasmid pRK792-encoding TEV protease (Addgene plasmid
#8830), the Georgia State University High Containment Core
and the Department for Animal Research for support, and
A. L. Hammond for critical reading of the manuscript.Funding:
This work was supported in part by Public Health Service grants
AI153400, AI071002, and AI141222 (to R.K.P.) from the NIH/NIAID.
The funders had no role in the study design, data collection
and interpretation, or the decision to submit the work for
publication.Author contributions:Conceptualization: M.G.N.,
G.R.P., and R.K.P. Investigation: J.S., R.M.C., M.T., J.Y., C.M.L.,
M.A., J.D.W., Z.S., and R.K.P. Resources: G.R.B., A.A.K., L.M.S., and
R.K.P. Visualization: G.R.B. and J.S. Validation: J.S. and R.K.P.
Funding acquisition: R.K.P. Project administration: M.G.N. and
R.K.P. Supervision: G.R.P. and R.K.P. Writing–original draft: J.S.
and R.K.P. Writing–review and editing: J.S. and R.K.P.Competing
interests:G.R.B. and G.R.P. are coinventors on patent WO 2019/

1736002 covering composition of matter and use of EIDD-2749

and its analogs as an antiviral treatment. This study could affect

their personal financial status. All other authors declare that they

have no competing interests.Data and materials availability:

All data are available in the main text or the supplementary

materials. Materials and methods are available as supplementary

materials at the Science website. Transfer of EIDD-2749 material

to other institutions for research purposes is covered by MTAs

from Emory University. This work is licensed under a Creative

Commons Attribution 4.0 International (CC BY 4.0) license, which

permits unrestricted use, distribution, and reproduction in any

medium, provided the original work is properly cited. To view a

copy of this license, visit https://creativecommons.org/licenses/

by/4.0/. This license does not apply to figures/photos/artwork or

other content included in the article that is credited to a third

party; obtain authorization from the rights holder before using

such material.

SUPPLEMENTARY MATERIALS

science.org/doi/10.1126/science.abj5508

Materials and Methods

Supplementary Text

Figs. S1 to S18

Tables S1 to S3

References ( 35 , 36 )

MDAR Reproducibility Checklist

Data S1 and S2

19 May 2021; resubmitted 4 October 2021

Accepted 29 November 2021

Published online 2 December 2021

10.1126/science.abj5508

NEURODEGENERATION

Cryo-EM structures of amyloid-b42 filaments from

human brains

Yang Yang^1 †, Diana Arseni^1 †, Wenjuan Zhang^1 †‡, Melissa Huang^1 , Sofia Lövestam^1 ,

Manuel Schweighauser^1 , Abhay Kotecha^2 , Alexey G. Murzin^1 , Sew Y. Peak-Chew^1 , Jennifer Macdonald^1 ,

Isabelle Lavenir^1 , Holly J. Garringer^3 , Ellen Gelpi^4 , Kathy L. Newell^3 , Gabor G. Kovacs4,5, Ruben Vidal^3 ,

Bernardino Ghetti^3 *, Benjamin Ryskeldi-Falcon^1 *, Sjors H. W. Scheres^1 *, Michel Goedert^1 *

Filament assembly of amyloid-bpeptides ending at residue 42 (Ab42) is a central event in Alzheimer’s

disease. Here, we report the cryo–electron microscopy (cryo-EM) structures of Ab42 filaments from

human brains. Two structurally related S-shaped protofilament folds give rise to two types of filaments.

Type I filaments were found mostly in the brains of individuals with sporadic Alzheimer’s disease,

and type II filaments were found in individuals with familial Alzheimer’s disease and other conditions.

The structures of Ab42 filaments from the brain differ from those of filaments assembled in vitro.

By contrast, inAppNL-Fknock-in mice, Ab42 deposits were made of type II filaments. Knowledge of Ab 42

filament structures from human brains may lead to the development of inhibitors of assembly

and improved imaging agents.

A

lzheimer’s disease is defined by the simul-

taneous presence of two different fil-

amentous amyloid inclusions in the

brain: abundant extracellular plaques of

amyloid-b(Ab) and intraneuronal neuro-

fibrillary tangles of tau ( 1 ). Genetic evidence

has indicated that Abis key to the pathogen-

esis of Alzheimer’s disease ( 2 , 3 ). Multiplications

of theAPPgene encoding the Abprecursor

protein, as well as mutations inAPPand in

PSEN1andPSEN2, the presenilin genes, cause

familial Alzheimer’s disease. Presenilins form

part of theg-secretase complex that is required

for the production of AbfromAPP. Although

variability ing-secretase cleavage results in

Abpeptides that vary in size, those of 40

(Ab40) and 42 (Ab42) amino acids are the

most abundant. Mutations associated with

familial Alzheimer’s disease increase the ratios

of Ab42 to Ab40 ( 4 , 5 ), the concentration of

Ab42 ( 6 ),and/ortheassemblyofAb42 into

filaments ( 7 ).

Three major types of Abinclusions are typ-

ical of the brain in Alzheimer’s disease ( 8 – 11 ):

diffuse and focal deposits in the parenchyma

as well as vascular deposits. Diffuse deposits,

which contain loosely packed Abfilaments,

are found in several brain regions, including

the entorhinal cortex, presubiculum, striatum,

brainstem, cerebellum, and subpial area. Focal

deposits, in the form of dense core plaques,

contain a spherical core of tightly packed Ab

filaments surrounded by more loosely packed

filaments. Dense core plaques are found mostly

in the hippocampus and cerebral cortex. In

advanced cases of Alzheimer’s disease, diffuse

and focal Abdeposits are widespread. In ~80%

of cases of Alzheimer’s disease, Abdeposits

are also found in the walls of blood vessels

(cerebral amyloid angiopathy). Cryo–electron

SCIENCEscience.org 14 JANUARY 2022•VOL 375 ISSUE 6577 167

(^1) Medical Research Council Laboratory of Molecular Biology,
Cambridge, UK.^2 Thermo Fisher Scientific, Eindhoven,
Netherlands.^3 Department of Pathology and Laboratory
Medicine, Indiana University, Indianapolis, IN, USA.^4 Institute
of Neurology, Medical University, Vienna, Austria.^5 Tanz
Centre and Department of Laboratory Medicine and
Pathobiology, University of Toronto, Toronto, ON, Canada.
*Corresponding author. Email: [email protected] (B.G.);
[email protected] (B.R.-F.); [email protected].
ac.uk (S.H.W.S.); [email protected] (M.G.)
†These authors contributed equally to this work.‡Present address:
Medical Research Council Prion Unit, Institute of Prion Diseases,
University College London, London, UK.
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