Identifying the Disease-Causing Form of the Amyloid Beta-Protein in Human Brain

Dominic Walsh, Bsc (Hons), PGCE, PhD
Brigham and Women's Hospital (Boston, MA)
Year Awarded:
2014
Grant Duration:
January 1, 2014 to December 31, 2016
Disease:
Alzheimer's
Award Amount:
$250,000
Grant Reference ID:
A2013059S
Award Type:
Standard
Award Region:
US Northeastern

Co-principal Investigators

Dennis J. C Selkoe, M.D.
Brigham and Women's Hospital

Coming to Grips with Brain-derived Water-soluble Aβ

Summary

Alzheimer’s disease (AD) is a devastating disorder for which there is no cure or effective treatment. A large weight of evidence suggests that a small protein, known as Abeta, plays a central role in causing AD, however, certain fundamental gaps in our knowledge about Abeta have been ignored or not rigorously addressed. Given the unsustainable burden that AD is now placing on healthcare systems worldwide and the limited resources that can be directed to research, it is essential that outstanding doubts about the role of Abeta in AD be directly and swiftly dealt with. In this proposal, we aim to tackle one central issue - the identification from the human brain of toxic forms of Abeta that cause AD.

Details

For many years the so-called “amyloid cascade hypothesis” has dominated Alzheimer’s disease (AD) research and shaped much of the thinking and drug development efforts in this field. However, for the first time in over a decade, substantial numbers of scientists have questioned the centrality of the beta-amyloid protein (Abeta) in AD. This has largely been driven by the failure of several clinical trials that were testing therapies targeting this protein. Although the trial designs and compounds investigated were imperfect, the negative outcomes from most of these trials are nonetheless worrisome and demand that we carefully re-evaluate the pathogenic role of Abeta in AD. Given the huge amount of effort that has been dedicated to developing anti-Abeta therapies, it would be foolhardy to dismiss advanced leads already in the pipeline, but it would also be inexcusable to persist with research on the wrong target. Thus, it is evident that regardless of whether or not Abeta ultimately proves to be a good target, an inappropriate decision either way on whether to maintain a high level of effort on Abeta research could have serious consequences for the many millions of present and future AD patients who need an effective therapy. In short, there is an urgent need to directly and swiftly clarify the role of Abeta in AD.

The team of Drs. Walsh and Selkoe is employing a unique constellation of methods and expertise in peptide chemistry and biophysics to tackle the central issue of identifying the toxic forms of Abeta present in the human brain that help to cause AD. The outcome of the team’s studies are likely to have two far-reaching effects. First, the identification and characterization of toxic forms of Abeta from humans will then facilitate a rigorous test of the fundamental unresolved questions about Abeta’s role in AD. The results of this test will either encourage the field to continue Abeta-directed therapies or to stop and look for alternatives. Either way, the results from these studies will have a huge influence on drug development efforts. The second far-reaching effect will come into play if the team confirms a causal link between certain forms of Abeta and AD. This may lead to new insight into the mechanism of AD, which could facilitate the development of novel therapies and useful diagnostic biomarkers.

About the Researcher

Dominic M. Walsh, Ph.D., is an Associate Professor at Brigham & Women’s Hospital and Harvard Medical School, and visiting Professor at the Institute of Neurology at University College London. He began working on Alzheimer’s disease in 1992 and gained postdoctoral training in Ireland and the US. With support from the Wellcome Trust he established the Laboratory for Neurodegenerative Research at University College Dublin in 2003 and in September 2011 moved his lab to the Harvard Institutes of Medicine in Boston. Prof. Walsh’s lab applies a wide range of advanced biochemical, molecular, cell biological, electrophysiological and behavioural methods to decipher the basic mechanisms of neurodegeneration. The ultimate goal of his research is to generate sufficient information to allow the development of rationally designed drugs that will slow or halt disease. As such he has been at the forefront of studies on the role of soluble A-beta oligomers in Alzheimer's disease and has authored several landmark papers. The impact and pace of his work is evident from the fact that twenty of his publications have each been cited in excess of 200 times and that more than a third of the total were published since 2007. Prof. Walsh has also written a number of widely cited reviews and has given over 80 invited lectures and webinars. He has served as an Editor or Editorial Advisor for several journals and as an ad hoc reviewer for all of the world’s leading biomedical journals. His research has been supported by the Wellcome Trust, European Union, Science Foundation Ireland, Health Research Board, IRCSET, Medical Research Council (UK), NIH (USA), Alzheimer’s Association (USA), grants from industry and donations from the general public. Prof. Walsh has provided expert analysis of Alzheimer disease research on TV and radio and has worked tirelessly to highlight the need for more investment in clinical and research services. He was the co-founder of the Dublin Brain Bank and is a member of the Irish National Steering Committee on Neurodegenerative Disease Research. Prof. Walsh has also organized several international conferences and has acted as a grant reviewer for more than 20 different agencies in the US, Europe, Middle East and Australia. He has served on the scientific advisory board of several start-up companies and is a consultant to a number of leading pharmaceutical companies.