Andersson E, Lindblom N, Janelidze S, Salvadó G, Gkanatsiou E, Söderberg L, Möller C, Lannfelt L, Ge J, Hanrieder J, Blennow K, Deierborg T, Mattsson-Carlgren N, Zetterberg H, Gouras G, Hansson O. Soluble cerebral Aβ protofibrils link Aβ plaque pathology to changes in CSF Aβ42/Aβ40 ratios, neurofilament light and tau in Alzheimer's disease model mice. Nat Aging. 2025 Feb 12; Epub 2025 Feb 12 PubMed.
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Brigham and Women's Hospital, Harvard Medical School
This interesting paper follows 30 years of the highly reproduced finding that the quantity of Aβ extracted from AD cortex in aqueous buffer, and retained in the supernatant after centrifugation (here termed protofibrils), correlates better with cognitive symptoms, tau pathology, and other downstream measures, compared to the amount of Aβ that enters the pellet or the number of amyloid plaques visible histologically. Here the authors nicely complement these findings in a detailed study of mouse models throughout the lifespan, paying particular attention to the Aβ42/40 CSF ratio and the aqueously extracted brain ratio anticorrelate, implying that similar factors control both. I would agree with the authors that a “soaking up” of newly generated monomers into these aqueously extractable aggregates could prevent the monomers from entering the CSF.
These aqueously extracted Aβ aggregates have been given several names—oligomers, protofibrils, amyloid-derived diffusible ligands (ADDLs), and others. The term “protofibril” in particular has a structural implication—i.e., that the atomic structure of a protofibril is different from that of a fibril, and precedes it during aggregation from monomer. Amyloid fibrils have a strict structural definition: β-sheet-rich planar monomers stacked 4.8 Å apart, held together by intermolecular backbone hydrogen bonding and intramolecular side chain interactions.
On the other hand, no such rigorous structural definition for a protofibril has been proposed in the literature, let alone one solved—they are so far defined only by molecular weight, not structure. One argument for a “non-fibrillar” structure comes from binding amyloid PET ligands and thioflavin dyes, but these are not necessarily reliable indicators of amyloid fibrils in isolation. Patients with the Arctic mutation have minimal amyloid PET signal, but pathology shows definite amyloid plaques with amyloid fibrils present by electron microscopy (Philipson et al., 2012), and their fibrillar structure has been solved by cryoEM (Yang et al., 2023).
We have found that what is extracted in aqueous buffer from human AD cortex is pelleted at sufficient centrifugal force, and possesses amyloid fibrils like in the conventionally insoluble fraction (Stern et al., 2023). Rather than make a structural claim, as the term “protofibril” implies, I would put forward that the Aβ more easily extracted in aqueous buffer reflects more diffusible amyloid fibrils that possess different isoforms/post-translational modifications, or binding partners, or are less compacted by a glial response, or are simply more recently formed, compared to the core. These other factors—modifications, binding partners, diffusibility, accumulation rate, etc.—may explain their toxicity rather than some non-fibrillar structure. This “all-fibril” model would be consistent with the observation that lecanemab, which purportedly targets protofibrils, exhibits approximately the same clinical efficacy and amyloid PET clearance as donanemab, which does not.
I may be wrong, and a clear, distinct, protofibrillar structure of Aβ may emerge with improvements in extraction and analysis—we can only see what our techniques allow. It is important to look for one. At this moment, however, protofibrils, as distinct from amyloid fibrils, are not necessary to explain the observations in this paper or others.
References:
Philipson O, Lord A, Lalowski M, Soliymani R, Baumann M, Thyberg J, Bogdanovic N, Olofsson T, Tjernberg LO, Ingelsson M, Lannfelt L, Kalimo H, Nilsson LN. The Arctic amyloid-β precursor protein (AβPP) mutation results in distinct plaques and accumulation of N- and C-truncated Aβ. Neurobiol Aging. 2012 May;33(5):1010.e1-13. Epub 2011 Nov 26 PubMed.
Yang Y, Zhang W, Murzin AG, Schweighauser M, Huang M, Lövestam S, Peak-Chew SY, Saito T, Saido TC, Macdonald J, Lavenir I, Ghetti B, Graff C, Kumar A, Nordberg A, Goedert M, Scheres SH. Cryo-EM structures of amyloid-β filaments with the Arctic mutation (E22G) from human and mouse brains. Acta Neuropathol. 2023 Mar;145(3):325-333. Epub 2023 Jan 7 PubMed.
Stern AM, Yang Y, Jin S, Yamashita K, Meunier AL, Liu W, Cai Y, Ericsson M, Liu L, Goedert M, Scheres SH, Selkoe DJ. Abundant Aβ fibrils in ultracentrifugal supernatants of aqueous extracts from Alzheimer's disease brains. Neuron. 2023 Jul 5;111(13):2012-2020.e4. Epub 2023 May 10 PubMed.
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