Dominic M. Walsh & Dennis
J. Selkoe talk with ScienceWatch.com and answer a
few questions about this month's Emerging Research Front in
the field of Neuroscience & Behavior.
Article: Naturally secreted oligomers of amyloid
beta protein potently inhibit hippocampal long-term
potentiation in vivo
DM;Klyubin, I;Fadeeva, JV;Cullen, WK;Anwyl, R;Wolfe,
Journal: NATURE, 416 (6880): 535-539 APR 4 2002
Addresses: Harvard Univ, Sch Med, Dept Neurol, Boston, MA
Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115
Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115
Univ Dublin Trinity Coll, Dept Pharmacol & Therapeut,
Dublin 2, Ireland.
(addresses may have been truncated.)
Why do you think your paper is highly
There are two key reasons: firstly,
Alzheimer's Disease (AD) involves compromise of
synaptic function and memory and, in this paper, we demonstrate that
certain forms of the AD-associated amyloid ß-protein (Aß)
can compromise long-term potentiation (LTP), a measure of synaptic
efficacy and a correlate of memory and learning.
Secondly, Aß can self-associate and aggregate to form a number of
different structural assemblies and there has been much contention as to
which of these species are pathogenic. In Walsh et al. we provide clear
evidence that a soluble non-fibrillar form of cell-derived Aß can
perturb LTP in the rat.
Does it describe a new discovery, methodology, or
synthesis of knowledge?
The methods used were not novel, but their application was new, i.e., we
tested the effect of two discrete types of Aß (monomer and SDS-stable
low-n oligomers) on LTP.
Would you summarize the significance of your paper in
This work suggests that the amyloid ß-protein is responsible for the
memory loss that characterizes AD.
How did you become involved in this research and were
any particular problems encountered along the way?
Professor Selkoe undertook a research fellowship after completing his
medical degree and training as a neurologist. Professor Walsh studied
biochemistry as an undergraduate and then completed a Ph.D. in
biochemistry. Both Professors Selkoe and Walsh have spent their working
life researching the molecular basis of AD.
Where do you see your research leading in the
Our research efforts are aimed to elucidate the molecular events which
trigger AD in the hope that we can identify useful therapeutic targets.
Do you foresee any social or political implications for
AD is a growing scourge which places a huge burden on society and health
care providers. Without an effective treatment this burden will steadily
increase as the world's population continues to age. Thus it is essential
that useful new therapeutics be developed as rapidly as possible. By
highlighting the role of soluble Aß in AD we hope we may have speeded
Dominic M. Walsh, Ph.D.
Associate Professor of Neurodegeneration
Laboratory for Neurodegenerative Research
School of Biomolecular and Biomedical Science
Conway Institute of Biomolecular and Biomedical Research
University College Dublin
Belfield, Dublin, Republic of Ireland
Dennis J. Selkoe M.D.
Center for Neurologic Diseases
Brigham and Women's Hospital
Harvard Institutes of Medicine
Boston, MA, USA
Keywords: naturally secreted oligomers, amyloid beta
protein, amyloid ß-protein, hippocampal long-term potentiation,
Alzheimer's Disease (AD), AD-associated amyloid ß-protein (Aß),
can compromise long-term potentiation (LTP), synaptic efficacy,