The work reported is the first demonstration that soluble cell-derived oligomers of the amyloid b-protein (Ab) can impair normal neuronal function. This is important because although there is extensive evidence implicating a central role for Ab in Alzheimer's disease (AD) questions concerning the physical properties of the species that mediate toxicity had previously been unresolved. Prior work had demonstrated that fibrillar Ab akin to that present in amyloid plaques (one of the characteristic lesions of AD) are neurtoxic both in vivo and in vitro. However levels of fibrillar Ab and degree of dementia correlate poorly, suggesting that non-fibrillar assemblies of Ab may be responsible for at least some aspects of the disease. In our study we found that injection of medium containing soluble oligomers of Ab into the brain of a live rat caused the loss of a neuronal activity associated with memory and learning.

Our work is unique in that it combines the use of a malleable cell culture system for the production of separable assembly forms of Ab and the measurement of hippocampal LTP in vivo.

  What were some of the circumstances that led you to do this research?

Prior work in our laboratory had shown that expression of genes that cause inheritable forms of AD also increase the level of oligomer formation, thus supporting the pathologic relevance of these assemblies.

  Could you summarize the significance of your paper in layman's terms?

There is overwhelming data to support a central role for Ab in Alzheimer's disease; therefore, understanding how this protein alters normal brain function should facilitate the development of effective therapies. Ab is unusual in that it can self-associate. First two molecules come together to form a dimer, then additional molecules add on forming trimers, tetramers, and so on. When significant numbers of Ab molecules self-associate they can be detected using high-powered microscopes and are evident in the brains of those afflicted with Alzheimer's. In our study we used immortalized cells that produce and secrete dimers and trimers (oligomers) of Ab. When injected into the brain of a live rat, oligomer-containing medium altered a neuronal activity associated with memory and learning. Compounds that lower production of Ab also prevented production of oligomers and thus abolished the associated alteration of neuronal activity. Thus our study suggests that lowering Ab to levels that prevent oligomerization may be a useful therapeutic strategy for the treatment of Alzheimer's disease.

Dominic M. Walsh, Ph.D.
Instructor in Neurology
Center for Neurologic Diseases
Harvard Institutes of Medicine
Boston, MA, USA