The manuscript by Crooks et al. describes cryo-EM structures and provides ssNMR data for filaments of synthetic wild-type Aβ40 peptides that were produced by seeded aggregation using seeds of vascular Aβ deposits extracted from brain sections of individuals with sporadic (wild-type Aβ Alzheimer’s disease) or inherited (E22Q Aβ, Dutch disease) cerebral amyloid angiopathy (CAA) by laser capture microdissection. Only one case of sporadic and one case of inherited CAA were used. The structures presented have some interesting similarities to, and some differences with, the Aβ40 structures that were previously described for non-amplified filaments from the leptomeninges of individuals with sporadic AD (Kollmer et al., 2019).
Crooks et al. interpret these differences with the (implicit) assumption that the filaments formed by seeded aggregation have the same structures as the initial seeds. As was previously shown for seeded aggregation of recombinant α-synuclein with seeds from the putamina of individuals with multiple system atrophy (MSA), seeded aggregation does not necessarily replicate the structures of the seeds (Lövestam et al., 2021). We recently also raised this point in regard to the manuscript by Fan et al. on seeded aggregation of recombinant α-synuclein with seeds from cerebrospinal fluid of individuals with Parkinson’s disease (Dec 2022 news). Because Crooks et al. provide no evidence to support their assumption that seeded aggregation replicated the seed structures, it is possible that the differences between the structures from seeds of sporadic and familial CAA, and the differences between these structures and those obtained by Kollmer et al. are due to artefacts of the seeded aggregation process.
This issue is ignored in the manuscript, which pitches structures of “human-derived fibrils” against structures obtained “in vitro.” However, we consider that the structures presented in this manuscript are themselves the result of in vitro assembly, albeit with the use of brain-derived seeds. We would therefore recommend a clearer distinction in the wording used to refer to structures of filaments that are extracted directly from human tissues (like the ones described by Kollmer et al.), structures of filaments of recombinant or synthetic proteins that are formed in vitro by seeded aggregation with brain-derived seeds (like the ones described by Crooks et al.), and the structures of filaments of recombinant or synthetic proteins from spontaneous in vitro aggregation.
References:
Kollmer M, Close W, Funk L, Rasmussen J, Bsoul A, Schierhorn A, Schmidt M, Sigurdson CJ, Jucker M, Fändrich M.
Cryo-EM structure and polymorphism of Aβ amyloid fibrils purified from Alzheimer's brain tissue.
Nat Commun. 2019 Oct 29;10(1):4760.
PubMed.
Lövestam S, Schweighauser M, Matsubara T, Murayama S, Tomita T, Ando T, Hasegawa K, Yoshida M, Tarutani A, Hasegawa M, Goedert M, Scheres SH.
Seeded assembly in vitro does not replicate the structures of α-synuclein filaments from multiple system atrophy.
FEBS Open Bio. 2021 Apr;11(4):999-1013. Epub 2021 Feb 24
PubMed.
The preprint at bioRXiv by Crooks et al. reports on the different structural properties of Aβ40 fibrils between an individual with sporadic CAA and an individual with familial CAA using cryo-EM and NMR. Although both structures shared a common fibrillar core, they differed in the fold of the N-terminal sequence. While one structure exhibited an ordered N-terminal fold comprised of two β-strands, the other structure showed a disordered N-terminus. The data may have relevance for potential pharmacological targets that distinguish amyloid aggregates in CAA from those within plaques. The authors argue that the binding properties of therapeutic anti-Aβ antibodies to vascular amyloid may explain the observed side effects such as hemorrhages in some of the treated AD patients.
On the other hand, soluble low-molecular weight oligomers and soluble protofibrils may prove better targets to prevent AD due to their higher toxicity. Therefore, it would make sense, in my view, to develop therapeutic antibodies or vaccines reacting against soluble aggregates of the amyloid cascade with a well-defined structure to avoid binding to CAA and plaques (see Mar 2022 news).
Comments
MRC Laboratory of Molecular Biology
MRC Laboratory of Molecular Biology
The manuscript by Crooks et al. describes cryo-EM structures and provides ssNMR data for filaments of synthetic wild-type Aβ40 peptides that were produced by seeded aggregation using seeds of vascular Aβ deposits extracted from brain sections of individuals with sporadic (wild-type Aβ Alzheimer’s disease) or inherited (E22Q Aβ, Dutch disease) cerebral amyloid angiopathy (CAA) by laser capture microdissection. Only one case of sporadic and one case of inherited CAA were used. The structures presented have some interesting similarities to, and some differences with, the Aβ40 structures that were previously described for non-amplified filaments from the leptomeninges of individuals with sporadic AD (Kollmer et al., 2019).
Crooks et al. interpret these differences with the (implicit) assumption that the filaments formed by seeded aggregation have the same structures as the initial seeds. As was previously shown for seeded aggregation of recombinant α-synuclein with seeds from the putamina of individuals with multiple system atrophy (MSA), seeded aggregation does not necessarily replicate the structures of the seeds (Lövestam et al., 2021). We recently also raised this point in regard to the manuscript by Fan et al. on seeded aggregation of recombinant α-synuclein with seeds from cerebrospinal fluid of individuals with Parkinson’s disease (Dec 2022 news). Because Crooks et al. provide no evidence to support their assumption that seeded aggregation replicated the seed structures, it is possible that the differences between the structures from seeds of sporadic and familial CAA, and the differences between these structures and those obtained by Kollmer et al. are due to artefacts of the seeded aggregation process.
This issue is ignored in the manuscript, which pitches structures of “human-derived fibrils” against structures obtained “in vitro.” However, we consider that the structures presented in this manuscript are themselves the result of in vitro assembly, albeit with the use of brain-derived seeds. We would therefore recommend a clearer distinction in the wording used to refer to structures of filaments that are extracted directly from human tissues (like the ones described by Kollmer et al.), structures of filaments of recombinant or synthetic proteins that are formed in vitro by seeded aggregation with brain-derived seeds (like the ones described by Crooks et al.), and the structures of filaments of recombinant or synthetic proteins from spontaneous in vitro aggregation.
References:
Kollmer M, Close W, Funk L, Rasmussen J, Bsoul A, Schierhorn A, Schmidt M, Sigurdson CJ, Jucker M, Fändrich M. Cryo-EM structure and polymorphism of Aβ amyloid fibrils purified from Alzheimer's brain tissue. Nat Commun. 2019 Oct 29;10(1):4760. PubMed.
Lövestam S, Schweighauser M, Matsubara T, Murayama S, Tomita T, Ando T, Hasegawa K, Yoshida M, Tarutani A, Hasegawa M, Goedert M, Scheres SH. Seeded assembly in vitro does not replicate the structures of α-synuclein filaments from multiple system atrophy. FEBS Open Bio. 2021 Apr;11(4):999-1013. Epub 2021 Feb 24 PubMed.
View all comments by Michel GoedertUniversity of Goettingen
The preprint at bioRXiv by Crooks et al. reports on the different structural properties of Aβ40 fibrils between an individual with sporadic CAA and an individual with familial CAA using cryo-EM and NMR. Although both structures shared a common fibrillar core, they differed in the fold of the N-terminal sequence. While one structure exhibited an ordered N-terminal fold comprised of two β-strands, the other structure showed a disordered N-terminus. The data may have relevance for potential pharmacological targets that distinguish amyloid aggregates in CAA from those within plaques. The authors argue that the binding properties of therapeutic anti-Aβ antibodies to vascular amyloid may explain the observed side effects such as hemorrhages in some of the treated AD patients.
On the other hand, soluble low-molecular weight oligomers and soluble protofibrils may prove better targets to prevent AD due to their higher toxicity. Therefore, it would make sense, in my view, to develop therapeutic antibodies or vaccines reacting against soluble aggregates of the amyloid cascade with a well-defined structure to avoid binding to CAA and plaques (see Mar 2022 news).
View all comments by Thomas BayerMake a Comment
To make a comment you must login or register.