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Lecanemab demonstrates highly selective binding to Aβ protofibrils isolated from Alzheimer's disease brains
Johannesson M, Söderberg L, Zachrisson O, Fritz N, Kylefjord H, Gkanatsiou E, Button E, Svensson AS et al.. Molecular and cellular neurosciences, 2024-06-20
Topic: Brain proteins, microglia and lab models
Recent advances in immunotherapeutic approaches to the treatment of Alzheimer's disease (AD) have increased the importance of understanding the exact binding preference of each amyloid-beta (Aβ) antibody employed, since this determines both efficacy and risk for potentially serious adverse events known as amyloid-related imaging abnormalities. Lecanemab is a humanized IgG1 antibody that was developed to target the soluble Aβ protofibril conformation. The present study prepared extracts of post mortem brain samples from AD patients and non-demented elderly controls, characterized the forms of Aβ present, and investigated their interactions with lecanemab. Brain tissue samples were homogenized and extracted using tris-buffered saline. Aβ levels and aggregation states in soluble and insoluble extracts, and in fractions prepared using size-exclusion chromatography or density gradient ultracentrifugation, were analyzed using combinations of immunoassay, immunoprecipitation (IP), and mass spectrometry. Lecanemab immunohistochemistry was also conducted in temporal cortex. The majority of temporal cortex Aβ (98 %) was in the insoluble extract. Aβ42 was the most abundant form present, particularly in AD subjects, and most soluble Aβ42 was in soluble aggregated protofibrillar structures. Aβ protofibril levels were much higher in AD subjects than in controls. Protofibrils captured by lecanemab-IP contained high levels of Aβ42 and lecanemab bound to large, medium, and small Aβ42 protofibrils in a concentration-dependent manner. Competitive IP showed that neither Aβ40 monomers nor Aβ40-enriched fibrils isolated from cerebral amyloid angiopathy reduced lecanemab's binding to Aβ42 protofibrils. Immunohistochemistry showed that lecanemab bound readily to Aβ plaques (diffuse and compact) and to intraneuronal Aβ in AD temporal cortex. Taken together, these findings indicate that while lecanemab binds to Aβ plaques, it preferentially targets soluble aggregated Aβ protofibrils. These are largely composed of Aβ42, and lecanemab binds less readily to the Aβ40-enriched fibrils found in the cerebral vasculature. This is a promising binding profile because Aβ42 protofibrils represent a key therapeutic target in AD, while a lack of binding to monomeric Aβ and cerebral amyloid deposits should reduce peripheral antibody sequestration and minimize risk for adverse events.
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APA 7th
Johannesson, M., Söderberg, L., Zachrisson, O., Fritz, N., Kylefjord, H., Gkanatsiou, E., et al. (2024). Lecanemab demonstrates highly selective binding to Aβ protofibrils isolated from Alzheimer's disease brains. Molecular and cellular neurosciences. https://doi.org/10.1016/j.mcn.2024.103949
Vancouver
Johannesson M, Söderberg L, Zachrisson O, Fritz N, Kylefjord H, Gkanatsiou E, et al. Lecanemab demonstrates highly selective binding to Aβ protofibrils isolated from Alzheimer's disease brains. Molecular and cellular neurosciences. 2024. doi:10.1016/j.mcn.2024.103949. PMID: 38906341.
BibTeX
@article{johannesson2024-38906341,
author = {Johannesson, M. and Söderberg, L. and Zachrisson, O. and Fritz, N. and Kylefjord, H. and Gkanatsiou, E. and Button, E. and Svensson, A. S. and others},
title = {{Lecanemab demonstrates highly selective binding to Aβ protofibrils isolated from Alzheimer's disease brains}},
journal = {Molecular and cellular neurosciences},
year = {2024},
doi = {10.1016/j.mcn.2024.103949},
pmid = {38906341},
url = {https://doi.org/10.1016/j.mcn.2024.103949}
}
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Key findings
- Competitive IP showed that neither Aβ40 monomers nor Aβ40-enriched fibrils isolated from cerebral amyloid angiopathy reduced lecanemab's binding to Aβ42 protofibrils.
- Immunohistochemistry showed that lecanemab bound readily to Aβ plaques (diffuse and compact) and to intraneuronal Aβ in AD temporal cortex.
- Taken together, these findings indicate that while lecanemab binds to Aβ plaques, it preferentially targets soluble aggregated Aβ protofibrils.
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Study details
- Evidence strengthLow
How this study scored 41/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 24 of the 58 points we could judge it on, which is 41 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Molecular and cellular neurosciences) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2024 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 38906341) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 24 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 24 of the 58 points we could judge it on is 41 out of 100. |
| Total | 41 / 100 | — |
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Also tagged “protofibrils”
2 studies in the library carry the topic tag “protofibrils”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 2 tagged studies.