The newly identified amyloid-beta intermediate forms (in orange/amber), the plaque-forming aggregates, and the protective BRICHOS chaperone proteins (in cyan/white) inside the brain's extracellular space.
Image Credit: Scientific Frontline / AI generated
Scientific Frontline: Extended "At a Glance" Summary: Amyloid-Beta Intermediates
The Core Concept: Researchers have identified two distinct, previously unknown intermediate clusters of the amyloid-beta protein that form before characteristic plaques develop in Alzheimer's disease.
Key Distinction/Mechanism: Although both newly discovered amyloid-beta forms are toxic to nerve cells, only one distinct cluster type continues to aggregate into full amyloid plaques, while the formation of both harmful forms can be actively counteracted by a chaperone protein known as BRICHOS.
Origin/History: An international collaborative study led by researchers at the Karolinska Institutet was published in Nature Communications on November 9, 2026, detailing the distinct aggregation pathways of these intermediates.
Major Frameworks/Components:
- Amyloid-beta aggregation pathways: Identification of small protein clusters that precede plaque formation, exhibiting distinct structural and pathological roles in the brain.
- Cellular toxicity models: Utilization of advanced microscopy, cultured nerve cells, mouse models, and human brain tissue to demonstrate how these specific protein forms damage neurons.
- BRICHOS protein intervention: A targeted therapeutic mechanism where the BRICHOS protein reduces the levels of toxic amyloid-beta forms, decreases neuroinflammation, and improves cognitive test performance.
Branches of Science: Molecular Neurobiology, Protein Biochemistry, Neuropathology, Neuropharmacology
Future Application: The BRICHOS protein could serve as a foundation for alternative therapeutic strategies, preventing the initial formation of toxic amyloid-beta forms rather than clearing established plaques with costly antibody treatments.
Why It Matters: Understanding the earliest stages of amyloid-beta aggregation provides a new, highly specific therapeutic target for Alzheimer's disease, potentially preventing irreversible nerve damage before widespread plaque formation occurs.
Researchers at Karolinska Institutet and their collaborators have identified two previously unknown forms of the protein amyloid-beta that may contribute to the development of Alzheimer's. The study, published in Nature Communications, also shows that the chaperone protein BRICHOS, previously identified by the team, can counteract the formation of these harmful forms, suggesting a potential new treatment approach.
Alzheimer's disease is the most common form of dementia. One protein that has long been a focus of research is amyloid-beta, which can clump together and form the plaques that characterize the disease.
In the new study, researchers from Karolinska Institutet, the University of Sheffield, and the University of Cambridge investigated small clusters of amyloid-beta that form before plaques develop. Using advanced microscopy and analyses of brain tissue from deceased people with Alzheimer's, as well as mouse models and cultured nerve cells, they identified two types of amyloid-beta clusters that can damage nerve cells.
Although both forms are capable of damaging nerve cells, researchers identified a key distinction: only one intermediate form appears to aggregate further into full amyloid plaques.
"We have identified two distinct forms of amyloid-beta that are present both in the brains of people with Alzheimer's disease and in our experimental models. Our findings show that they form in different ways and may play different roles in the progression of the disease," says Jan Johansson, professor at the Department of Medicine, Huddinge, Karolinska Institutet, and one of the study's lead researchers.
In mouse models, treatment with BRICHOS reduced the levels of these harmful forms. It also reduced plaque formation and inflammation in the brain while improving performance in cognitive tests.
While current antibody treatments targeting amyloid-beta are utilized for Alzheimer's, this research suggests an alternative therapeutic approach.
"Current antibody treatments for Alzheimer's have limited effects, can cause side effects, and are costly. Our findings suggest an alternative approach, aimed at preventing the formation of the forms of amyloid-beta that appear to cause the damage," says Jan Johansson.
More research is needed to understand the role these newly identified forms of amyloid-beta play in the progression of Alzheimer's. The next step is to investigate how they damage nerve cells and to further develop BRICHOS as a potential treatment.
Funding: This work was supported by the UKRI Future Leaders Fellowship (MR/V023861/1; E.F.G., A.U., and S.D.), the DiMeN Doctoral Training Partnership (MR/N013840/1; D.P.R., S.D.), an EPSRC PhD Studentship (2594676; H.E.W., S.D.), an Alzheimer’s Research UK PhD Studentship (ARUK-PhD2024-010; H.J.B., S.D.) and a Wellcome fellowship (216340/Z/19/Z; S.M.B.). Additional support was provided by the National Institute for Health and Care Research (NIHR) and the Sheffield Biomedical Research Centre (BRC).
Disclaimer: The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.
Published in journal: Nature Communications
Authors: Agnieszka Urbanek, Alexander J. Dear, David P. Rhodes, Emma F. Garland, Hollie E. Wareing, Harry J. Baker, Willem Molenkamp, Ruixin Zhang, Gefei Chen, Axel Abelein, Simon M. Bell, Juan A. Varela, Thomas C. T. Michaels, J. Robin Highley, Georg Meisl, Jan Johansson, and Suman De
Source/Credit: Karolinska Institutet
Edited by: Scientific Frontline
Reference Number: nbio110926_01
