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Diffusible, nonfibrillar ligands derived from Aβ 1–42 are potent central nervous system neurotoxins
Mary P. Lambert, Avlin K. Barlow, Brett A. Chromy, C. Edwards, R. Freed, M. Liosatos, Todd E. Morgan, Irina Rozovsky, Barbara L. Trommer, Kirsten L. Viola, P.A. Wals, C. Zhang, Caleb E. Finch, Grant A. Krafft, William L. Klein. Proceedings of the National Academy of Sciences, 1998-05-26
Topic: Brain proteins, microglia and lab models
Abeta1-42 is a self-associating peptide whose neurotoxic derivatives are thought to play a role in Alzheimer's pathogenesis. Neurotoxicity of amyloid beta protein (Abeta) has been attributed to its fibrillar forms, but experiments presented here characterize neurotoxins that assemble when fibril formation is inhibited. These neurotoxins comprise small diffusible Abeta oligomers (referred to as ADDLs, for Abeta-derived diffusible ligands), which were found to kill mature neurons in organotypic central nervous system cultures at nanomolar concentrations. At cell surfaces, ADDLs bound to trypsin-sensitive sites and surface-derived tryptic peptides blocked binding and afforded neuroprotection. Germ-line knockout of Fyn, a protein tyrosine kinase linked to apoptosis and elevated in Alzheimer's disease, also was neuroprotective. Remarkably, neurological dysfunction evoked by ADDLs occurred well in advance of cellular degeneration. Without lag, and despite retention of evoked action potentials, ADDLs inhibited hippocampal long-term potentiation, indicating an immediate impact on signal transduction. We hypothesize that impaired synaptic plasticity and associated memory dysfunction during early stage Alzheimer's disease and severe cellular degeneration and dementia during end stage could be caused by the biphasic impact of Abeta-derived diffusible ligands acting upon particular neural signal transduction pathways.
Why it matters
This lab study found that small, diffusible oligomers of amyloid beta 1-42 (called ADDLs) killed mature neurons in brain tissue cultures at nanomolar concentrations and inhibited hippocampal long-term potentiation before cells degenerated. The authors hypothesize these oligomers could underlie early memory dysfunction and later cell loss in Alzheimer's disease.
How this study scored 56/100
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 strength of evidence, so that was left out: it earned 53 of the 95 points we could judge it on, which is 56 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Proceedings of the National Academy of Sciences) |
| Journal's citation record | 4 / 4 | Proceedings of the National Academy of Sciences: journal h-index 1,167 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | — / 5 | No evidence rating recorded — left out of this score |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 1998 — older than 20 years, still counted |
| 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 / 7 | Cited 3,510 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 117.0 citations a year over 30 year(s) since 1998 |
| Impact for its field and year | 5 / 6 | Cited 29.3× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 4 / 4 | Cited 211 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author William L. Klein: h-index 79 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Northwestern University: institution h-index 1,592 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 9600986) |
| Free to read | 2 / 2 | Free to read |
| Points | 53 / 95 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 53 of the 95 points we could judge it on is 56 out of 100. |
| Total | 56 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record names 15 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
APA 7th
Lambert, M. P., Barlow, A. K., Chromy, B. A., Edwards, C., Freed, R., Liosatos, M., et al. (1998). Diffusible, nonfibrillar ligands derived from Aβ 1–42 are potent central nervous system neurotoxins. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.95.11.6448
Vancouver
Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, et al. Diffusible, nonfibrillar ligands derived from Aβ 1–42 are potent central nervous system neurotoxins. Proceedings of the National Academy of Sciences. 1998. doi:10.1073/pnas.95.11.6448. PMID: 9600986.
BibTeX
@article{lambert1998-9600986,
author = {Lambert, Mary P. and Barlow, Avlin K. and Chromy, Brett A. and Edwards, C. and Freed, R. and Liosatos, M. and Morgan, Todd E. and Rozovsky, Irina and Trommer, Barbara L. and Viola, Kirsten L. and Wals, P.A. and Zhang, C. and Finch, Caleb E. and Krafft, Grant A. and Klein, William L.},
title = {{Diffusible, nonfibrillar ligands derived from Aβ 1–42 are potent central nervous system neurotoxins}},
journal = {Proceedings of the National Academy of Sciences},
year = {1998},
doi = {10.1073/pnas.95.11.6448},
pmid = {9600986},
url = {https://doi.org/10.1073/pnas.95.11.6448}
}
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