While the amyloid hypothesis-that aggregates of Aβ peptide are the primary pathogen in AD-drives much of Alzheimer's disease research, it remains controversial as some observations have been difficult to reconcile with it. For example, the degree of dementia correlates only weakly with the burden of amyloid plaques in the brain at the time of death. Conversely, transgenic mice carrying the disease-causing human amyloid precursor protein (AβPP) exhibit synaptic, electrophysiological, and behavioral deficits before amyloid plaques form.
One line of thought holds that freely circulating Aβ, in the form of oligomers that have not yet formed large fibrillar aggregates, are the truly toxic species. Two papers in yesterdays’ Nature go a way toward showing how small amyloid aggregates could interfere with normal cellular function or even kill cells, not just in AD, but in other neurodegenerative diseases as well.
Dominic Walsh, working with Dennis Selkoe and colleagues at Harvard Medical School and at Trinity College in Dublin, Ireland, generated human Aβ (from the disease-causing V717F mutation of APP) in Chinese hamster ovary cells. First author Dominic Walsh et al. were able to show that soon after the synthesis of Aβ monomers, these single peptide species combined to form dimers, trimers, and perhaps even larger oligomers, which were subsequently secreted into the culture medium. The oligomers, but not the monomers, in this culture medium, were able to impair hippocampal long-term potentiation (LTP) when injected into rat brain. When the Aβ-secreting cells were treated with an inhibitor of the enzyme γ-secretase (which cleaves AβPP to form Aβ) the culture medium no longer contained Aβ oligomers (though it did contain monomers) and it no longer disrupted LTP. Since LTP is thought of as a mechanism of memory storage, these data support a candidate mechanism-and possible solution-for the memory deficits of AD, the authors write.
In the larger scope of degenerative disease, protein aggregates are implicated in spongiform encephalopathies, Parkinson's disease, and other neurological and non-neurological conditions. In the same issue of Nature, researchers from the University of Florence in Italy and the University of Cambridge in England show that several seemingly benign proteins not associated with any degenerative diseases can be toxic to cells in the early stages of aggregation. The researchers showed that during the early of stages of aggregation, when the protein has aggregated into small oligomers, it is highly toxic to cells in culture. Later, when highly structured fibrils have time to form, the cytotoxic effect disappears.
"Together, the [two studies] suggest that damage to cells can be caused by misfolded intermediates generated during the production of amyloid fibrils, whether or not the fibrils-or the normal proteins from which they are derived-are also toxic. The toxicity of these early aggregates depends upon some as-yet-undefined structural features, and not upon their amino acid sequence," write John Ellis and Teresa Pinheiro of the University of Warwick, in Covington, England, in an accompanying News and Views article.—Hakon Heimer
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- Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 2002 Apr 4;416(6880):535-9. PubMed.
- Bucciantini M, Giannoni E, Chiti F, Baroni F, Formigli L, Zurdo J, Taddei N, Ramponi G, Dobson CM, Stefani M. Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature. 2002 Apr 4;416(6880):507-11. PubMed.
- Ellis RJ, Pinheiro TJ. Medicine: danger--misfolding proteins. Nature. 2002 Apr 4;416(6880):483-4. PubMed.