26 August 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
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.), 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.
Reference:Nilsberth C, Westlind-Danielsson A, Eckman CB, Condron MM, Axelman K, Forsell C, Stenh C, Luthman J, Teplow DB, Younkin SG, Naslund J, Lannfelt L.
The "Arctic" APP mutation (E693G) causes Alzheimer's
disease by enhanced Ab protofibril formation. Nature Neuroscience 2001 Sept. Abstract
Online Forum: "Protofibrillar
Ab in Alzheimer's disease"