INSIGHTS | PERSPECTIVES
GRAPHIC: V. ALTOUNIAN/SCIENCEscience.org SCIENCE( 3 ). The peptide conformations in
these newly described Ab42 fibrils
were S shaped at the carboxyl ter-
minus and conformationally disor-
dered at the amino terminus. Their
conformations differ from the
C-shaped peptide conformation
and amino-terminal stability of
Ab40 fibrils from AD brain tissue
(see the figure). Instead, the fibril
peptides resemble the S-shaped
structures and amino-terminal dis-
order of Ab42 fibrils in vitro ( 5 – 7 ),
although none of these structures
exactly matched the peptide con-
formations reported by Yang et al.
This is in accordance with previ-
ous conclusions that in vitro fibrils
do not necessarily model the spe-
cific morphologies of ex vivo fibrils
(that were extracted from diseased
tissue) ( 3 , 8 – 10 ). Because ex vivo fi-
brils are typically more resistant to
proteolysis than many in vitro fi-
brils, it has been suggested that dis-
ease-associated amyloid fibril struc-
tures arose by proteolytic selection
in vivo ( 8 , 11 ). However, a general
concern of studying ex vivo fibrils
is whether the extraction procedure
might modify the fibril structure,
specifically if this procedure in-
volves 2% sarkosyl detergent, as in
the case of Yang et al. Yet, type I and
type II fibrils correlated with differ-
ent neurodegenerative conditions,
and details of their conformation
differed from previously described
in vitro structures ( 5 – 7 ), which in-
dicates that the observed fibrillar
morphologies are representative of
the fibrils deposited in brain tissue.
What do these structures mean
for the pathogenesis of AD? Most stud-
ies assume that prefibrillar oligomers of
Ab42, rather than Ab42 fibrils, constitute
the main pathogenic agents in AD ( 1 ).
Notably, the S-shaped peptide fold in the fi-
brils described by Yang et al. resembles the
S-shaped peptide conformation that was
previously suggested for an Ab42 oligomer
( 12 ). Genetic analyses of AD risk genes and
longitudinal brain imaging studies plus
ever-more-sensitive biomarker analyses
indicate that the formation of fibrils and
amyloid plaques occurs as early as 20 years
before AD patients develop cognitive symp-
toms ( 13 ). After many failures of Ab-directed
therapeutic trials for AD, there is debate
about the benefit of vaccination against ag-
gregated Ab. Therefore, gathering molecular
insights on Ab plaque composition is impor-
tant to develop such vaccines. Hopefully, the
molecular insights on Ab structures ( 3 , 4 ),
and similar knowledge obtained from other
neurodegeneration-associated fibril struc-
tures, such as those derived from tau ( 9 ) and
TAR DNA-binding protein 43 (TDP-43) ( 10 ),
will aid in understanding the mechanism of
neurodegenerative diseases and may gener-
ate new therapeutic or diagnostic strategies.
Antibodies are capable of reducing Ab
load in AD patients, but it remains un-
known whether they are the right tools
to break down oligomers and fibrils. The
Ab42 fibrils described by Yang et al. are
conformationally disordered at the amino
terminus, which harbors the epitopes tar-
geted by many therapeutic antibodies,
such as amino acids 3 to 7, recognized by
the antibody aducanumab ( 14 ). The con-
formational disorder observed at this site
indicates that this part of the fibrillar pro-
tein is particularly accessible for antibody
binding. The conformational disorder maystem, at least partly, from the nu-
merous posttranslational modifica-
tions (PTMs) that affect the amino
terminus of Ab ( 2 ). PTMs are not
included in the stable conformation
of type I and type II Ab42 fibrils,
but detailed knowledge about the
variability and the extent of spe-
cific PTMs in oligomeric Ab and fi-
brillar Ab will be instrumental for
the development of inhibitors of
fibril formation or drugs to break
up amyloid plaques.
Molecular imaging with positron
emission tomography with ligands
that are based on the fibril-binding
molecule thioflavin currently al-
lows for the in vivo visualization
and tracking of pathophysiological
changes in AD and mild cognitive
impairment ( 15 ). However, thiofla-
vin derivatives may not differen-
tially bind all relevant fibril types
of Ab, and therefore, new ligands
with higher sensitivity and specific-
ity are desirable for personalized
medicine approaches. Moreover,
Ab seeding strategies, which allow
the formation of amyloid fibrils in
mice in a short amount of time,
could be an alternative approach
to test breakers of amyloid fibrils
in vivo. But another important goal
should be to determine the pat-
terns of oligomers, protofilaments,
and coaggregating molecules, such
as apolipoprotein E, to better tar-
get them for disease prevention.
The currently available structures
of different ex vivo Ab fibrils may
open the door to develop such next-
generation amyloid ligands. jREFERENCES AND NOTES- C. Haass, D. J. Selkoe, Nat. Rev. Mol. Cell Biol. 8 , 101
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ACKNOWLEDGMENTS
M.F. is supported by the German Research Council
(FA456/24-1).10.1126/science.abn5428Ab 40Ab 42
Ty p e IType IIVa l^40Gly^9Asp^1Ala^42Ala^42Va l^12148 14 JANUARY 2022 • VOL 375 ISSUE 6577
Amyloid fibril structures
Cryo–electron microscopy (cryo-EM)–derived structures of
fibrils formed from amyloid-b40 (Ab40) ( 3 ) and Ab42 ( 4 )
from human brain tissue reveal different polymer conformations that
are associated with distinct neurodegenerative diseases.