26 Aug 2001

The dominant theory of Alzheimer's disease is that insoluble aggregates of amyloid-β (Aβ) are the neurotoxic entity that causes neuronal dysfunction and cell death. Proponents of this theory argue that the genetic evidence provides very strong support: namely, that mutations that cause autosomal dominant, early onset AD have been linked to an increase in Aβ42-putatively the most toxic form of the peptide-as compared to Aβ40.

However, critics of the theory point out that plaque density in AD does not correlate well with the severity of dementia or neurodegeneration. What's more, several familial AD mutations, notably the "Arctic," "Flemish," "Italian," and "Dutch" mutations, all of which involve codons (692 or 693) near the α cleavage site, affect Aβ processing in ways that do not fit neatly with the theory. The Arctic mutation, for example, actually lowers plasma levels of Aβ40 and 42.

How to account for this apparent paradox? The answer may reside in "protofibrils" or "ADDLs" according to a report by Nilsberth et al. in the September issue of Nature Neuroscience. "Protofibrils and ADDLs are small assemblies of Aβ peptide, first described several years ago" (Walsh et al. 1997, Harper et al. 1997, and Lambert et al. 1998), that are important intermediary molecules in Aβ aggregation and are known to cause selective neuronal death in vitro (Walsh et al. 1999, Hartley et al. 1999, Ward et al., 2000)." In cell cultures, Nilsberth, et al., determined that although the Arctic mutation results in reduced Aβ42, the mutation also caused accelerated production of protofibrils. The authors note that plasma Aβ levels are not increased in sporadic AD, and suggest that protofibrils may be a hitherto overlooked pathogenic mechanism for certain familial as well as sporadic forms of AD. It remains to be seen whether protofibrils are critical to Alzheimer's pathology in humans, but the new finding bolsters an emerging view that there is more to plaque than meets the eye.—June Kinoshita

Online Forum: "Protofibrillar Ab in Alzheimer's disease"