Summary: Two new studies shed light on the most toxic forms of amyloid beta and suggest how researchers can find new antibodies to help target these structures in Alzheimer’s disease.
Source: Brigham and Women’s Hospital.
Two new studies published by investigators from Brigham and Women’s Hospital illustrate that not all forms of amyloid-beta (Aβ) protein – the protein thought to initiate Alzheimer’s disease – play an equally menacing role in the progress of the disease. Using a new way of preparing and extracting the protein as well as a new technique to search for promising drug candidates, researchers have highlighted the importance of testing and targeting different forms of Aβ. Their work may help advance the search for more precise and effective drugs to prevent or halt the progress of Alzheimer’s disease.
“Many different efforts are currently underway to find treatments for Alzheimer’s disease, and anti-Aβ antibodies are currently the furthest advanced. But the question remains: what are the most important forms of Aβ to target? Our study points to some interesting answers,” said Dominic Walsh, PhD, a principal investigator in the Ann Romney Center.
Aβ protein can take forms ranging from monomers – single molecules – to twisted tangles of plaques that can pollute the brain and are large enough that they can be seen with a traditional microscope. Walsh compares monomers to single Lego bricks, which can start sticking together to form complex structures of varying sizes. The two recently published studies investigate how to find new potential therapeutics that can target the structures most likely to cause harm.
Most Alzheimer’s disease studies use synthetic Aβ to approximate what conditions in the brain of an Alzheimer’s patient might be like. A small number of researchers have used Aβ extracted from human brain, but the extraction process is crude. In a study published in Acta Neuropathologica in April, Walsh and colleagues developed a much gentler extraction protocol to prepare samples from subjects with Alzheimer’s disease. The team found that Aβ was far more abundant in traditional crude extracts, but that the bulk of the extracted Aβ was innocuous. In contrast, much less Aβ was obtained with the gentler protocol, but in this case most of the Aβ was toxic.
In a second study published in Nature Communications in July, Walsh and colleagues developed a screening test to try to find potential drugs to target the toxic forms of Aβ. The new technique uses extracts of brain samples from Alzheimer’s disease patients and live-cell imaging of stem-cell derived brain cells to find promising therapeutics. The team reports on 1C22, an Aβ antibody that they found could protect against toxic forms of amyloid-beta more effectively than the most clinically advanced Alzheimer’s disease therapeutics currently in clinical trials.
“We anticipate that this primary screening technique will be useful in the search to identify more potent anti-Aβ therapeutics in the future,” said Walsh.
Funding: Funding for the study appearing in Acta Neuropathologica was provided by the National Institutes of Health (AG046275), Bright Focus, and by the Massachusetts Alzheimer’s Disease Research Center (AG05134). Funding for the study appearing in Nature Communications was provided by the National Institute on Aging (AG046275, AG006173 and AG015379), Health Research Board Ireland (Grant RP/2008/30) and Bright Focus.
Source: Haley Bridger – Brigham and Women’s Hospital
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Open access research for “An in vitro paradigm to assess potential anti-Aβ antibodies for Alzheimer’s disease” by Ming Jin, Brian O’Nuallain, Wei Hong, Justin Boyd, Valentina N. Lagomarsino, Tiernan T. O’Malley, Wen Liu, Charles R. Vanderburg, Matthew P. Frosch, Tracy Young-Pearse, Dennis J. Selkoe & Dominic M. Walsh in Nature Communications. Published July 11 2018.
doi:10.1038/s41467-018-05068-w
Abstract for “Diffusible, highly bioactive oligomers represent a critical minority of soluble Aβ in Alzheimer’s disease brain” by Wei Hong, Zemin Wang, Wen Liu, Tiernan T. O’Malley, Ming Jin, Michael Willem, Christian Haass, Matthew P. Frosch, and Dominic M. Walsh in Acta Neuropathologica. Published July 2018.
doi:10.1007/s00401-018-1846-7
[cbtabs][cbtab title=”MLA”]Brigham and Women’s Hospital”Advancing the Search for Antibodies to Treat Alzheimer’s.” NeuroscienceNews. NeuroscienceNews, 30 July 2018.
<https://neurosciencenews.com/alzheimers-antibodies-9630/>.[/cbtab][cbtab title=”APA”]Brigham and Women’s Hospital(2018, July 30). Advancing the Search for Antibodies to Treat Alzheimer’s. NeuroscienceNews. Retrieved July 30, 2018 from https://neurosciencenews.com/alzheimers-antibodies-9630/[/cbtab][cbtab title=”Chicago”]Brigham and Women’s Hospital”Advancing the Search for Antibodies to Treat Alzheimer’s.” https://neurosciencenews.com/alzheimers-antibodies-9630/ (accessed July 30, 2018).[/cbtab][/cbtabs]
Abstract
An in vitro paradigm to assess potential anti-Aβ antibodies for Alzheimer’s disease
Although the amyloid β-protein (Aβ) is believed to play an initiating role in Alzheimer’s disease (AD), the molecular characteristics of the key pathogenic Aβ forms are not well understood. As a result, it has proved difficult to identify optimal agents that target disease-relevant forms of Aβ. Here, we combined the use of Aβ-rich aqueous extracts of brain samples from AD patients as a source of human Aβ and live-cell imaging of iPSC-derived human neurons to develop a bioassay capable of quantifying the relative protective effects of multiple anti-Aβ antibodies. We report the characterization of 1C22, an aggregate-preferring murine anti-Aβ antibody, which better protects against forms of Aβ oligomers that are toxic to neurites than do the murine precursors of the clinical immunotherapeutics, bapineuzumab and solanezumab. These results suggest further examination of 1C22 is warranted, and that this bioassay maybe useful as a primary screen to identify yet more potent anti-Aβ therapeutics.
Abstract
Diffusible, highly bioactive oligomers represent a critical minority of soluble Aβ in Alzheimer’s disease brain
Significant data suggest that soluble Aβ oligomers play an important role in Alzheimer’s disease (AD), but there is great confusion over what exactly constitutes an Aβ oligomer and which oligomers are toxic. Most studies have utilized synthetic Aβ peptides, but the relevance of these test tube experiments to the conditions that prevail in AD is uncertain. A few groups have studied Aβ extracted from human brain, but they employed vigorous tissue homogenization which is likely to release insoluble Aβ that was sequestered in plaques during life. Several studies have found such extracts to possess disease-relevant activity and considerable efforts are being made to purify and better understand the forms of Aβ therein. Here, we compared the abundance of Aβ in AD extracts prepared by traditional homogenization versus using a far gentler extraction, and assessed their bioactivity via real-time imaging of iPSC-derived human neurons plus the sensitive functional assay of long-term potentiation. Surprisingly, the amount of Aβ retrieved by gentle extraction constituted only a small portion of that released by traditional homogenization, but this readily diffusible fraction retained all of the Aβ-dependent neurotoxic activity. Thus, the bulk of Aβ extractable from AD brain was innocuous, and only the small portion that was aqueously diffusible caused toxicity. This unexpected finding predicts that generic anti-oligomer therapies, including Aβ antibodies now in trials, may be bound up by the large pool of inactive oligomers, whereas agents that specifically target the small pool of diffusible, bioactive Aβ would be more useful. Furthermore, our results indicate that efforts to purify and target toxic Aβ must employ assays of disease-relevant activity. The approaches described here should enable these efforts, and may assist the study of other disease-associated aggregation-prone proteins.
